Abstract

Aims

This study investigated the effects of irbesartan vs. enalapril, with early vs. late treatment, on markers of inflammation and ischaemic heart disease in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS).

Methods and results

Patients hospitalized with ischaemic symptoms and evidence of NSTEACS were randomized to early (at hospitalization) or late (at hospital discharge) treatment with irbesartan 150 mg/day followed by 300 mg/day on day 15 (n = 212) or enalapril 10 mg/day followed by 20 mg/day on day 15 (n = 217) to day 60. The primary endpoint was the change from baseline in high-sensitivity C-reactive protein (hs-C-reactive protein) at day 60; secondary endpoints included changes in troponin I, B-type natriuretic peptide, microalbuminuria, interleukin 6, myeloperoxidase, secretory non-pancreatic type II phospholipase A2, ischaemia-modified albumin, soluble CD40 ligand, matrix metalloproteinase-9, aldosterone, and blood pressure. High-sensitivity C-reactive protein levels were comparable in both the irbesartan and enalapril treatment arms. There were no treatment-related differences in any of the biomarkers measured. Changes in inflammatory markers were unaffected by the timing of treatment initiation. Both treatments were well tolerated, with no differences in major adverse cardiac events.

Conclusion

In patients with NSTEACS, inflammatory markers decreased over time in both treatment arms, with no differences between irbesartan and enalapril.

Introduction

Acute coronary syndrome (ACS) is commonly caused by rupture of an atherosclerotic plaque induced by inflammatory stress in atherosclerotic coronary vessels.1,2 Systemic and local pro-inflammatory factors appear to activate the endothelium and trigger plaque rupture, initiating thrombosis and inducing ACS.3–5 Cellular and biochemical markers of inflammation have been found to be elevated in ACS and correlate with clinical outcome. Elevated levels of high-sensitivity C-reactive protein (hs-C-reactive protein) are associated with higher mortality rates, a poorer prognosis, and an increased need for revascularization in patients with ACS.6–14 C-reactive protein also correlates with other biomarkers of inflammation, cardiovascular disease, and endothelial dysfunction with demonstrated prognostic value following ACS events. For example, troponin I1,11,15–17 (a marker for cardiac necrosis), B-type natriuretic peptide (BNP)1,9,11,17–19 (a marker for left ventricular remodelling), and microalbuminuria20,21 (a marker for endothelial dysfunction) have all been shown in clinical studies to predict future mortality and/or cardiovascular events in patients with ACS. Drugs that can attenuate oxidative stress by reducing levels of inflammatory and other cardiovascular biomarkers may therefore play an important role in the treatment of ACS. Aspirin reduces circulating levels of C-reactive protein, interleukin 6 (IL-6), and macrophage colony-stimulating factor in people with stable angina,22 and statins have been shown to attenuate C-reactive protein and other markers of inflammation independent of their effects on lipid lowering.23–29 Because the renin–angiotensin–aldosterone system (RAAS) plays an important role in inflammation,30 drugs that inhibit the RAAS, such as angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme-inhibitors (ACE-Is), may have the potential to significantly improve the outcome of patients with ACS.

Several studies have demonstrated benefits for both ARBs and ACE-Is in post-myocardial infarction (MI) patients,31–33 and RAAS blockade is a standard component of post-MI therapy.15 Although there is no formal indication for patients with non-ST-segment elevation ACS (NSTEACS), the American Heart Association/American College of Cardiology guidelines recommend administering an ACE-I, or an ARB if patients are ACE-I intolerant, within the first 24 h in hospitalized patients with NSTEACS and evidence of heart failure and/or impaired left ventricular function.15 Early initiation of RAAS inhibition appears to be important in influencing ACS outcomes. In a post hoc analysis of patients with NSTEACS in the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study, ACE inhibition was beneficial when started early in reducing the occurrence of death and severe congestive heart failure.34

The ARB irbesartan has been shown in several studies to reduce inflammatory markers in patients with coronary artery disease (CAD). One month of treatment with irbesartan 300 mg/day significantly reduced plasma concentrations of C-reactive protein in patients with unstable angina,35 and in a separate 3 month study, irbesartan but not enalapril significantly reduced IL-6, hs-C-reactive protein, and platelet aggregation compared with baseline in 48 patients with CAD and hypertension following coronary angioplasty.36

The main objectives of this study were to compare the effects of irbesartan and enalapril on inflammatory markers in patients hospitalized with NSTEACS, and to evaluate whether there is a benefit to early or late initiation of treatment. Secondary objectives looked at the same comparisons on other key prognostic cardiovascular markers.

Methods

Design overview

Patients with NSTEACS were randomized to irbesartan or enalapril on hospital admission (early initiation) or at hospital discharge (late initiation) until day 60 (Figure 1).

Figure 1

ARCHIPELAGO study design.

Figure 1

ARCHIPELAGO study design.

Setting and participants

The study was conducted in 63 centres in 11 countries (USA, Canada, Belgium, The Netherlands, Germany, Italy, Switzerland, Spain, Hungary, UK, and France). The first patient enrolled in February 2006 and the last patient completed in March 2007. Adults aged ≥18 years who were hospitalized with ischaemic symptoms (last episode within the last 48 h before randomization) and at least one of the following characteristics of NSTEACS were eligible for the study: electrocardiographic (ECG) ST or T changes (ST depression or transient elevation of at least 1 mm or T-wave changes in at least two leads) or positive troponin test (assessed according to the local threshold). Exclusion criteria included patients with persistent ST-segment elevation on ECG, coronary angiography or angioplasty planned before baseline sampling, concomitant cardiovascular or renal disease, serum potassium >5.5 mmol/L, creatinine clearance ≤30 mL/min (based on serum creatinine value at admission by applying the Cockcroft and Gault formula), congestive heart failure with New York Heart Association class III or IV symptoms, angioplasty, surgery or trauma within the last 3 months, systolic blood pressure (SBP) <100 mmHg, fever (≥38°C), concomitant infection, chronic inflammatory disease, cancer in evolution, non-steroidal anti-inflammatory drug or steroid use, administration of an ARB or ACE-I within the previous 3 days, or any investigational study drug within the previous 30 days.

This study was conducted in accordance with the ethical principles originating from the current Declaration of Helsinki and was consistent with International Conference on Harmonization Good Clinical Practice and applicable regulatory requirements. The institutional review board/Ethics Committee of each participating site approved the study. All patients gave written informed consent before enrolment.

Randomization and interventions

This was a randomized, double-blind, double-dummy, 2 × 2 factorial, phase 3b, 2 month study. Eligible patients were randomized using a central randomized system (interactive voice response system). The randomization schedule stratified patients according to the presence or not of diabetes. Within each stratum, patients were randomized in a 1:1 ratio to either irbesartan 150 mg once daily (od) on admission to hospital (early initiation) or at hospital discharge (late initiation) followed by irbesartan 300 mg od from day 15 to day 60 (study end), or to enalapril 10 mg od started early or late, force-titrated to 20 mg od from day 15 onward (Figure 1).

To ensure blinding, the active study medications were dispensed in two dose levels (irbesartan 150 mg, then 300 mg; enalapril 10 mg, then 20 mg), with matching placebos. Medication was taken in the morning unless a visit was scheduled for that day. Physical examinations, including blood pressure (measured three times after at least 3 min rest) and pulse rate, were carried out at each visit, and patients self-monitored blood pressure every morning and evening during the study.

Biological markers with a known predictive clinical value in patients with ACS were assessed during the study, including markers of inflammation [hs-C-reactive protein, IL-6, myeloperoxidase (MPO), and secretory non-pancreatic type II phospholipase A2 (sPLA2)]; matrix metalloproteinase-9 (MMP-9); myocardial ischaemia [ischaemia-modified albumin (IMA)]; platelet activation [soluble CD40 ligand (sCD40L)]; left ventricular dysfunction (BNP); myocardial necrosis (troponin I); endothelial dysfunction (microalbuminuria, 30–300 mg urine albumin/g creatinine); and RAAS (aldosterone). All biological markers were evaluated at a central laboratory. Serum creatinine and potassium were evaluated locally at every visit; if creatinine clearance <30 mL/min and/or potassium >5.5 mmol/L, treatment was stopped and the patient followed for safety until the 2 month visit. Other safety parameters (liver enzymes—aspartate amino transferase/alanine amino transferase, red and white blood cell count, thrombocytes, bilirubin, and haemoglobin) were measured on admission to hospital (baseline) and at every study visit.

Outcomes and follow-up

The primary efficacy endpoint was the change from baseline in hs-C-reactive protein at day 60 ± 7. Secondary efficacy outcomes included change from baseline in hs-C-reactive protein at discharge; changes from baseline to discharge and to day 60 in IL-6, sCD40L, sPLA2, MMP-9, MPO, BNP, troponin I, IMA, microalbuminuria, and aldosterone; and the change from baseline in blood pressure at discharge, day 15, and day 60. For all the listed parameters, the effects of early vs. late initiation of treatment were evaluated.

Safety was monitored at every scheduled visit by assessing all causes of death; bleeding; hypotension; renal insufficiency and hyperkalaemia; blood pressure and heart rate; the incidence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, MI, stroke, hospitalization for recurrent ischaemia, or urgent revascularization; and the incidence of heart failure.

Statistical analysis

A sample size of 216 subjects in each of the two treatment groups was estimated as sufficient to provide 80% power and a two-sided 0.05 significance level to detect a between-group difference in the change from baseline in hs-C-reactive protein at day 60 ± 7. On the basis of the results of previous small studies,35–37 a difference of 25% with a standard deviation of 87.5% and a maximum of 10% non-evaluable patients for the primary endpoint at day 60 ± 7 was assumed. Efficacy and safety data were analysed for the intent-to-treat (ITT) population, comprising all patients who received at least one dose of study medication. A last-observation-carried-forward approach was used to replace missing data. The main statistical model was based on a full factorial design with two main factors: the treatment effect of irbesartan vs. enalapril and the time to treatment effect early vs. late treatment, and used the absolute change from baseline as the dependent variable in an ANCOVA model with the baseline value as covariate. If the interaction between drug effect and time to treatment effect was not significant at P = 0.10, then each main effect was tested at P = 0.05 in the same model without the interaction term and adjusted on the baseline value. To take into account multiplicity testing (treatment effect and time to treatment effect), P-values for the primary criteria have been adjusted using Hochberg method in order to control type-I error of the study.38

Secondary efficacy analysis also took into account diabetes as a co-variable using three-factor ANCOVA, as it was pre-defined in the protocol. Continuous variables were summarized using tables of descriptive statistics, including the number of observations available (n), the mean, standard deviation, minimum, and maximum. Qualitative variables were summarized using counts and percentages. In general, treatment groups were compared using t-test for continuous data and χ2 or Fisher exact test for qualitative variables.

Results

A total of 429 patients were included in the study, 212 in the irbesartan arm and 217 in the enalapril arm (ITT population) (Figure 2). There were 64 and 59 discontinuations in the irbesartan and enalapril arms, respectively. Compliance was good with only two patients (enalapril group) who discontinued because of poor or non-compliance.

Figure 2

Summary of patient randomization and flow through the study.

Figure 2

Summary of patient randomization and flow through the study.

Patient baseline characteristics and demographics are shown in Table 1. The majority of patients (87.3% irbesartan; 84.3% enalapril) had a history of cardiovascular disease. On admission, 54.1% of patients were receiving cardiovascular drugs, including lipid-lowering agents (40.5%), heparins (49.4%), and anti-platelet agents (52.9%), with no differences between the treatment groups. Coronary angiography was planned in >80% of the patients (82.5 and 83.4% in the irbesartan and enalapril groups, respectively).

Table 1

Baseline demographics and patient characteristics

Parameter Irbesartan
 
Enalapril
 
Early (n = 105) Late (n = 107) Early (n = 107) Late (n = 110) 
Age in years, mean (SD) 62.2 (11.5) 60.9 (12.8) 62.4 (11.5) 60.9 (11.8) 

 
Sex (%patients) 
 Male 76 76 67 77 
 Female 24 24 33 23 

 
Height in cm, mean (SD) 171 (8.9) 170.5 (10.3) 170.3 (8.9) 170.6 (9.8) 
Weight in kg, mean (SD) 81.7 (15.2) 78.6 (14.7) 80.5 (15.3) 80.2 (17.6) 
Waist circumference in cm, mean (SD) 98.9 (15.3) 98.6 (12.6) 99.1 (11.5) 97.8 (13.3) 

 
Cardiovascular history (%patients) 
 Patients with a history of one or more cardiovascular symptoms/conditions 85.7 88.8 88.8 80.0 
 Hypertension 47.6 56.1 43.0 40.0 
 Hyperlipidaemia 53.3 48.6 46.7 48.2 
 Current smoker 29.5 31.8 34.6 42.7 
 Diabetes 14.3 13.1 13.1 12.7 
 Previous angina 28.6 43.0 27.1 21.8 
 Previous cardiac intervention 18.1 18.7 12.1 10.0 
 Previous MI 14.3 15.9 7.5 9.1 
 Symptomatic peripheral arterial disease 3.8 4.7 5.6 10.9 
 Previous ischaemic stroke 7.6 4.7 2.8 2.7 
 Dysrhythmia 10.5 5.6 6.5 5.5 
 Heart failure 1.0 1.9 3.6 
 Other evidence of CAD 5.7 11.2 1.9 3.6 

 
Ischaemic symptoms—ECG findings (%patients) 
 T-wave modifications 41.9 48.6 53.3 50.0 
 Depression of ST-segment 47.6 37.4 32.7 30.9 
 Transient elevation of ST-segment 7.6 9.3 13.1 10.0 
 Left bundle branch block 1.9 0.9 1.9 1.8 
 Q-waves 10.5 14.0 13.1 6.4 
 Other 5.7 6.5 9.3 2.7 

 
Ischaemic symptoms—elevated locally assessed enzymes (%patients) 
 Creatine kinasea 18.1 15.9 15.0 18.2 
 Creatine kinase MB fractiona 8.6 13.1 9.3 10.9 
 Troponin I 76.2 72.9 73.8 86.4 
Parameter Irbesartan
 
Enalapril
 
Early (n = 105) Late (n = 107) Early (n = 107) Late (n = 110) 
Age in years, mean (SD) 62.2 (11.5) 60.9 (12.8) 62.4 (11.5) 60.9 (11.8) 

 
Sex (%patients) 
 Male 76 76 67 77 
 Female 24 24 33 23 

 
Height in cm, mean (SD) 171 (8.9) 170.5 (10.3) 170.3 (8.9) 170.6 (9.8) 
Weight in kg, mean (SD) 81.7 (15.2) 78.6 (14.7) 80.5 (15.3) 80.2 (17.6) 
Waist circumference in cm, mean (SD) 98.9 (15.3) 98.6 (12.6) 99.1 (11.5) 97.8 (13.3) 

 
Cardiovascular history (%patients) 
 Patients with a history of one or more cardiovascular symptoms/conditions 85.7 88.8 88.8 80.0 
 Hypertension 47.6 56.1 43.0 40.0 
 Hyperlipidaemia 53.3 48.6 46.7 48.2 
 Current smoker 29.5 31.8 34.6 42.7 
 Diabetes 14.3 13.1 13.1 12.7 
 Previous angina 28.6 43.0 27.1 21.8 
 Previous cardiac intervention 18.1 18.7 12.1 10.0 
 Previous MI 14.3 15.9 7.5 9.1 
 Symptomatic peripheral arterial disease 3.8 4.7 5.6 10.9 
 Previous ischaemic stroke 7.6 4.7 2.8 2.7 
 Dysrhythmia 10.5 5.6 6.5 5.5 
 Heart failure 1.0 1.9 3.6 
 Other evidence of CAD 5.7 11.2 1.9 3.6 

 
Ischaemic symptoms—ECG findings (%patients) 
 T-wave modifications 41.9 48.6 53.3 50.0 
 Depression of ST-segment 47.6 37.4 32.7 30.9 
 Transient elevation of ST-segment 7.6 9.3 13.1 10.0 
 Left bundle branch block 1.9 0.9 1.9 1.8 
 Q-waves 10.5 14.0 13.1 6.4 
 Other 5.7 6.5 9.3 2.7 

 
Ischaemic symptoms—elevated locally assessed enzymes (%patients) 
 Creatine kinasea 18.1 15.9 15.0 18.2 
 Creatine kinase MB fractiona 8.6 13.1 9.3 10.9 
 Troponin I 76.2 72.9 73.8 86.4 

SD, standard deviation; MI, myocardial infarction; CAD, coronary artery disease; ECG, electrocardiograph.

aMore than twice upper normal limit.

For 212 patients (n = 105 irbesartan; n = 107 enalapril), treatment was initiated early, and for 217 patients (n = 107 irbesartan; n = 110 enalapril), treatment was initiated late.

Efficacy

High-sensitivity C-reactive protein levels

High-sensitivity C-reactive protein levels at baseline and day 60 in the irbesartan and enalapril treatment arms are shown in Figure 3 and Tables 2 and 3. High-sensitivity C-reactive protein levels over the study period were comparable in both treatment groups (mean ± SD, irbesartan: 15.2 ± 30.2 mg/L at baseline, 6.5 ± 17.4 mg/L at day 60; absolute change of −8.7 ± 32.3 mg/L; enalapril: 12.6 ± 26.4 mg/L at baseline, 5.5 ± 11.4 mg/L at day 60; absolute change of −7.1 ± 26.2 mg/L, NS). This was so for early initiation of treatment (irbesartan: 17.1 ± 33.9 mg/L at baseline, 5.3 ± 13.9 mg/L at day 60; change of −11.7 ± 35.1 mg/L; enalapril: 13.5 ± 29.4 mg/L at baseline, 6.3 ± 13.3 mg/L at day 60; change of −7.3 ± 29.7 mg/L, NS) and for treatment initiated later (at hospital discharge) (irbesartan: 13.5 ± 26.1 mg/L at baseline, 7.7 ± 20.2 mg/L at day 60; change of –5.7 ± 30.1 mg/L; enalapril: 11.7 ± 23.2 mg/L at baseline, 4.8 ± 9.2 mg/L at day 60; change of−6.9 ± 23.4 mg/L; NS) (Table 2). The interaction between treatment and the timing of treatment initiation was not significantly different (P = 0.16, Table 2). There was no significant difference between irbesartan and enalapril treatments in the change in hs-C-reactive protein from baseline to discharge.

Figure 3

Evolution of mean high-sensitivity C-reactive protein levels from baseline to day 60 (intent-to-treat population) among patients with acute coronary syndrome treated for 2 months with irbesartan or enalapril. Values are mean ± SEM.

Figure 3

Evolution of mean high-sensitivity C-reactive protein levels from baseline to day 60 (intent-to-treat population) among patients with acute coronary syndrome treated for 2 months with irbesartan or enalapril. Values are mean ± SEM.

Table 2

Absolute change from baseline in high-sensitivity C-reactive protein at day 60 according to early or late initiation

hs-C-reactive protein, mg/mL Irbesartan (n = 212) Enalapril (n = 217) P-value 
Early initiation, mean values (SD) −11.7 (35.1) −7.3 (29.7)  
Late initiation, mean values (SD) −5.7 (30.1) −6.9 (23.4)  
Adjusted difference (95% CI): irbesartan–enalapril 0.79 (−1.99 to 3.57)  0.64* 
Adjusted difference (95% CI): early–late interaction −0.67 (−3.45 to 2.11)  0.64* 
Interaction between irbesartan/enalapril initiated early or late   0.16 
hs-C-reactive protein, mg/mL Irbesartan (n = 212) Enalapril (n = 217) P-value 
Early initiation, mean values (SD) −11.7 (35.1) −7.3 (29.7)  
Late initiation, mean values (SD) −5.7 (30.1) −6.9 (23.4)  
Adjusted difference (95% CI): irbesartan–enalapril 0.79 (−1.99 to 3.57)  0.64* 
Adjusted difference (95% CI): early–late interaction −0.67 (−3.45 to 2.11)  0.64* 
Interaction between irbesartan/enalapril initiated early or late   0.16 

*P-value after adjustment for multi-test with the Hochberg method.

Table 3

Mean absolute change from baseline at day 60 in inflammatory markers and other markers of cardiovascular disease (intent-to-treat population)

 Irbesartan (n = 212)
 
Enalapril (n = 217)
 
P-value 
 Baseline Day 60 Mean absolute change Baseline Day 60 Mean absolute change 
Inflammatory markers 
 hs-C-reactive protein, mg/mL 15.2 (30.2) 6.5 (17.4) −8.7 (32.3) 12.6 (26.4) 5.5 (11.4) −7.1 (26.6) 0.58 (0.16) 
  Early 17.1 (33.9) 5.3 (13.9) −11.7(35.1) 13.5 (29.4) 6.3 (13.3) −7.3 (29.7) 
  Late 13.5 (26.1) 7.7 (20.2) −5.7 (30.1) 11.7 (23.2) 4.8 (9.2) −6.9 (23.4) 
 IL-6, pg/mL 14.8 (26.3) 6.1 (12.5) −8.6 (24.9) 12.8 (24.8) 5.3 (6.1) −7.5 (25.1) 0.48 (0.45) 
  Early 17.2 (30.1) 7.5 (17.2) −9.6 (28.2) 11.2 (24.1) 5.6 (6.1) −5.5 (24.1) 
  Late 12.3 (21.8) 4.8 (4.3) −7.5 (21.2) 14.4 (25.5) 5.0 (6.0) −9.3 (26.0) 
 MMP-9, ng/mL 58.4 (41.7) 40.8 (26.0) −17.6 (35.9) 62.6 (40.1) 43.7 (29.5) −18.6 (37.7) 0.46 (0.13) 
  Early 61.7 (48.6) 39.6 (26.5) −21.9 (40.6) 61.3 (4.05) 45.0 (30.5) −16.2 (38.6) 
  Late 55.1 (33.3) 42.0 (25.5) −13.3 (30.2) 63.8 (39.8) 42.4 (28.5) −21.0 (36.9) 
 MPO, ng/mL 44.8 (103.6) 28.1 (89.7) −16.6 (47.7) 43.0 (60.4) 28.0 (49.0) −14.9 (0.2) 0.73 (0.54) 
  Early 49.1 (135.2) 33.2 (125.9) −15.8 (34.1) 44.0 (56.9) 28.5 (28.2) −15.5 (54.3) 
  Late 40.4 (56.4) 23.0 (20.9) −17.4 (58.5) 41.9 (63.9) 27.5 (63.1) −14.3 (17.6) 
 sPLA2, ng/mL 6.65 (12.85) 3.94 (3.63) −2.70 (12.6) 6.48 (23.23) 3.97 (4.58) −2.47 (23.1) 0.28 (0.34) 
  Early 7.01 (13.93) 3.75 (36.82) −3.27 (13.75) 7.03 (27.61) 4.71 (58.75) −2.30 (27.25) 
  Late 6.28 (11.74) 4.13 (35.75) −2.13 (11.47) 5.93 (17.99) 3.26 (26.46) −2.65 (18.23) 

 
Other markers 
 sCD40L, ng/mL 3.4 (2.9) 5.4 (3.5) 2.0 (3.8) 3.7 (3.0) 5.8 (4.1) 2.0 (4.3) 0.54 (0.61) 
  Early 3.3 (2.5) 5.4 (3.5) 2.2 (3.9) 3.9 (3.2) 5.7 (3.9) 1.8 (4.1) 
  Late 3.6 (3.2) 5.4 (3.4) 1.8 (3.8) 3.5 (2.9) 5.8 (4.2) 2.3 (4.6) 
 Troponin I, ng/mL 3.1 (6.1) 0.4 (2.3) −2.7 (5.8) 3.4 (10.9) 0.3 (1.4) −3.2 (10.4) 0.43 (0.29) 
  Early 3.2 (6.8) 0.6 (3.1) −2.6 (6.3) 2.5 (6.1) 0.2 (0.7) −2.3 (6.2) 
  Late 3.0 (5.4) 0.2 (1.0) −2.8 (5.4) 4.4 (14.1) 0.4 (1.8) −4.0 (13.3) 
 IMA, IU/mL 99.0 (25.6) 85.9 (21.4) −13.0 (30.6) 100.8 (33.9) 87.4 (15.3) −13.4 (31.9) 0.51 (0.87) 
  Early 98.8 (16.5) 89.6 (23.8) −9.2 (26.4) 98.3 (19.8) 88.8 (14.9) −9.6 (21.3) 
  Late 99.2 (32.3) 82.3 (18.1) −16.7 (34.0) 103.2 (43.5) 86.0 (15.6) −17.1 (39.3) 
 BNP, pg/mL 144.5 (192.3) 116.3 (174.9) −27.9 (165.9) 140.3 (177.7) 91.9 (113.4) −48.0 (144.0) 0.06 (0.66) 
  Early 136.7 (165.3) 115.1 (170.4) −20.9 (179.3) 154.7 (218.5) 95.7 (113.9) −58.0 (181.6) 
  Late 152.3 (216.4) 117.5 (179.9) −34.9 (151.8) 126.2 (125.6) 88.2 (113.3) −38.3 (93.8) 
 Microalbuminuria, mg/L 33.4 (147.4) 38.2 (280.5) 0.8 (243.9) 23.0 (76.4) 19.3 (61.4) −2.9 (51.5) 0.78 (0.17) 
  Early 32.8 (107.8) 62.0 (395.9) 22.4 (299.4) 31.7 (100.2) 23.9 (81.6) −6.9 (65.3) 
  Late 33.9 (178.8) 14.5 (31.8) −20.6 (171.2) 14.6 (41.9) 15.0 (31.8) 0.9 (33.4) 
 Aldosterone, pg/mL 60.9 (48.3) 70.6 (50.7) 10.6 (58.9) 61.7 (66.8) 69.7 (66.3) 8.2 (81.6) 0.74 (0.74) 
  Early 61.7 (50.6) 68.6 (54.3) 7.4 (60.2) 60.5 (66.2) 68.7 (75.5) 8.3 (87.0) 
  Late 60.1 (46.0) 72.5 (47.0) 13.7 (57.8) 62.8 (67.7) 70.7 (56.4) 8.0 (76.5) 
 Irbesartan (n = 212)
 
Enalapril (n = 217)
 
P-value 
 Baseline Day 60 Mean absolute change Baseline Day 60 Mean absolute change 
Inflammatory markers 
 hs-C-reactive protein, mg/mL 15.2 (30.2) 6.5 (17.4) −8.7 (32.3) 12.6 (26.4) 5.5 (11.4) −7.1 (26.6) 0.58 (0.16) 
  Early 17.1 (33.9) 5.3 (13.9) −11.7(35.1) 13.5 (29.4) 6.3 (13.3) −7.3 (29.7) 
  Late 13.5 (26.1) 7.7 (20.2) −5.7 (30.1) 11.7 (23.2) 4.8 (9.2) −6.9 (23.4) 
 IL-6, pg/mL 14.8 (26.3) 6.1 (12.5) −8.6 (24.9) 12.8 (24.8) 5.3 (6.1) −7.5 (25.1) 0.48 (0.45) 
  Early 17.2 (30.1) 7.5 (17.2) −9.6 (28.2) 11.2 (24.1) 5.6 (6.1) −5.5 (24.1) 
  Late 12.3 (21.8) 4.8 (4.3) −7.5 (21.2) 14.4 (25.5) 5.0 (6.0) −9.3 (26.0) 
 MMP-9, ng/mL 58.4 (41.7) 40.8 (26.0) −17.6 (35.9) 62.6 (40.1) 43.7 (29.5) −18.6 (37.7) 0.46 (0.13) 
  Early 61.7 (48.6) 39.6 (26.5) −21.9 (40.6) 61.3 (4.05) 45.0 (30.5) −16.2 (38.6) 
  Late 55.1 (33.3) 42.0 (25.5) −13.3 (30.2) 63.8 (39.8) 42.4 (28.5) −21.0 (36.9) 
 MPO, ng/mL 44.8 (103.6) 28.1 (89.7) −16.6 (47.7) 43.0 (60.4) 28.0 (49.0) −14.9 (0.2) 0.73 (0.54) 
  Early 49.1 (135.2) 33.2 (125.9) −15.8 (34.1) 44.0 (56.9) 28.5 (28.2) −15.5 (54.3) 
  Late 40.4 (56.4) 23.0 (20.9) −17.4 (58.5) 41.9 (63.9) 27.5 (63.1) −14.3 (17.6) 
 sPLA2, ng/mL 6.65 (12.85) 3.94 (3.63) −2.70 (12.6) 6.48 (23.23) 3.97 (4.58) −2.47 (23.1) 0.28 (0.34) 
  Early 7.01 (13.93) 3.75 (36.82) −3.27 (13.75) 7.03 (27.61) 4.71 (58.75) −2.30 (27.25) 
  Late 6.28 (11.74) 4.13 (35.75) −2.13 (11.47) 5.93 (17.99) 3.26 (26.46) −2.65 (18.23) 

 
Other markers 
 sCD40L, ng/mL 3.4 (2.9) 5.4 (3.5) 2.0 (3.8) 3.7 (3.0) 5.8 (4.1) 2.0 (4.3) 0.54 (0.61) 
  Early 3.3 (2.5) 5.4 (3.5) 2.2 (3.9) 3.9 (3.2) 5.7 (3.9) 1.8 (4.1) 
  Late 3.6 (3.2) 5.4 (3.4) 1.8 (3.8) 3.5 (2.9) 5.8 (4.2) 2.3 (4.6) 
 Troponin I, ng/mL 3.1 (6.1) 0.4 (2.3) −2.7 (5.8) 3.4 (10.9) 0.3 (1.4) −3.2 (10.4) 0.43 (0.29) 
  Early 3.2 (6.8) 0.6 (3.1) −2.6 (6.3) 2.5 (6.1) 0.2 (0.7) −2.3 (6.2) 
  Late 3.0 (5.4) 0.2 (1.0) −2.8 (5.4) 4.4 (14.1) 0.4 (1.8) −4.0 (13.3) 
 IMA, IU/mL 99.0 (25.6) 85.9 (21.4) −13.0 (30.6) 100.8 (33.9) 87.4 (15.3) −13.4 (31.9) 0.51 (0.87) 
  Early 98.8 (16.5) 89.6 (23.8) −9.2 (26.4) 98.3 (19.8) 88.8 (14.9) −9.6 (21.3) 
  Late 99.2 (32.3) 82.3 (18.1) −16.7 (34.0) 103.2 (43.5) 86.0 (15.6) −17.1 (39.3) 
 BNP, pg/mL 144.5 (192.3) 116.3 (174.9) −27.9 (165.9) 140.3 (177.7) 91.9 (113.4) −48.0 (144.0) 0.06 (0.66) 
  Early 136.7 (165.3) 115.1 (170.4) −20.9 (179.3) 154.7 (218.5) 95.7 (113.9) −58.0 (181.6) 
  Late 152.3 (216.4) 117.5 (179.9) −34.9 (151.8) 126.2 (125.6) 88.2 (113.3) −38.3 (93.8) 
 Microalbuminuria, mg/L 33.4 (147.4) 38.2 (280.5) 0.8 (243.9) 23.0 (76.4) 19.3 (61.4) −2.9 (51.5) 0.78 (0.17) 
  Early 32.8 (107.8) 62.0 (395.9) 22.4 (299.4) 31.7 (100.2) 23.9 (81.6) −6.9 (65.3) 
  Late 33.9 (178.8) 14.5 (31.8) −20.6 (171.2) 14.6 (41.9) 15.0 (31.8) 0.9 (33.4) 
 Aldosterone, pg/mL 60.9 (48.3) 70.6 (50.7) 10.6 (58.9) 61.7 (66.8) 69.7 (66.3) 8.2 (81.6) 0.74 (0.74) 
  Early 61.7 (50.6) 68.6 (54.3) 7.4 (60.2) 60.5 (66.2) 68.7 (75.5) 8.3 (87.0) 
  Late 60.1 (46.0) 72.5 (47.0) 13.7 (57.8) 62.8 (67.7) 70.7 (56.4) 8.0 (76.5) 

P-value for treatment effect; P-values for interaction between irbesartan/enalapril initiated early or late are given in parentheses.

Values at baseline and day 60 are mean (standard deviation).

IL-6, interleukin 6; sCD40L, soluble CD40 ligand; MMP-9, matrix metalloproteinase-9; MPO, myeloperoxidase; sPLA2, secretory non-pancreatic type-II phospholipase A2; IMA, ischaemia-modified albumin; BNP, B-type natriuretic peptide.

Other inflammatory and cardiovascular markers

Mean levels of inflammatory markers (IL-6, MMP-9, MPO, and sPLA2) decreased between baseline and day 60 to a comparable extent in both treatment groups (Table 3), regardless of time of treatment initiation. Interactions between irbesartan/enalapril treatment initiated early or late were not significant (Table 3). Similarly, mean levels of markers of myocardial injury (troponin I), ischaemia (IMA) and dysfunction (BNP), and endothelial dysfunction (microalbuminuria) also decreased from baseline to day 60, with no significant differences between treatment groups. Mean levels of aldosterone (a marker of RAAS activity) and sCD40L (a marker of thrombosis) did not change significantly from baseline to day 60 with either treatment.

Blood pressure

Mean blood pressure remained essentially unchanged throughout the study. In the irbesartan group, mean ± SD SBP/diastolic blood pressure (DBP) was 130.5 ± 19.0/74.9 ± 12.1 mmHg at baseline and 128.1 ± 17.9/76.0 ± 10.4 mmHg at day 60. In the enalapril group, SBP/DBP values were 129.2 ± 18.0/73.3 ± 11.3 mmHg at baseline and 130.4 ± 17.7/76.4 ± 10.5 mmHg at day 60. There were no significant changes in either group during the study. Overall, 22 (10.4%) patients in the irbesartan group and 11 (5.1%) patients in the enalapril group (P = 0.04) discontinued the study because of an SBP <100 mmHg.

Safety

The number of MACE during the study is summarized in Table 4; there were no significant differences between the two treatment groups. There were two cardiovascular deaths in the irbesartan group and three in the enalapril group. These were not drug related. Both irbesartan and enalapril were well tolerated, with no unexpected adverse events.

Table 4

Major adverse cardiovascular events

Events Irbesartan (n = 212) Enalapril (n = 217) P-value 
Number of MACE events 20 15  
 Number of patients with one or more events, n (%) 16 (7.5) 13 (6.0) 0.52 
  Cardiovascular death 2 (0.9) 3 (1.4) 1.0 
  Myocardial infarctiona 9 (4.2) 5 (2.3) 0.26 
  Stroke  
  Hospitalization for recurrent angina 4 (1.9) 5 (2.3) 1.0 
  Hospitalization for urgent revascularization 4 (1.9) 2 (0.9) 0.45 
  Heart failureb 1 (0.5) 3 (1.4) 0.62 
Events Irbesartan (n = 212) Enalapril (n = 217) P-value 
Number of MACE events 20 15  
 Number of patients with one or more events, n (%) 16 (7.5) 13 (6.0) 0.52 
  Cardiovascular death 2 (0.9) 3 (1.4) 1.0 
  Myocardial infarctiona 9 (4.2) 5 (2.3) 0.26 
  Stroke  
  Hospitalization for recurrent angina 4 (1.9) 5 (2.3) 1.0 
  Hospitalization for urgent revascularization 4 (1.9) 2 (0.9) 0.45 
  Heart failureb 1 (0.5) 3 (1.4) 0.62 

MACE indicates cardiovascular death, myocardial infarction, stroke, and hospitalization for recurrent angina or urgent revascularization.

aOne patient had two episodes of myocardial infarction.

bHeart failure was not adjudicated.

There were no statistically or clinically significant changes in any laboratory safety parameters during the study, including creatinine levels.

Discussion

ARCHIPELAGO (Acute coronary syndromes Randomized to a Controlled evaluation in the first Hours of presentation with Irbesartan vs. enalapril to Prevent Elevated inflammation, Limit myocardial ischemia And Generate better Outcome) is the largest randomized study comparing the effect of two different blockers of the RAAS on biological markers of inflammation and myocardial ischaemia, damage, and function in NSTEACS. In this 2 month study, hs-C-reactive protein levels from baseline to day 60 were similar in both the irbesartan and enalapril treatment arms. Previous studies have shown that irbesartan reduces markers of inflammation in normotensive patients with early atherosclerosis,39 in patients with stable coronary heart disease receiving aspirin and statins,40,41 and in patients with metabolic syndrome.37 Our results indicate that ARBs do not provide any differential benefit on inflammatory markers compared with ACE-Is.

Although the present study did not include a placebo group and so the changes in C-reactive protein levels shown may reflect the natural course of hs-C-reactive protein in NSTEACS, other studies have shown a reduction in C-reactive protein levels with ARBs against placebo; Biasucci et al.35 showed that in 25 patients with NSTEACS receiving aspirin, clopidogrel, and statins, irbesartan 300 mg/day for 1 month significantly reduced plasma C-reactive protein levels and appeared to reduce IL-6 in vitro generation after liposaccharide challenge, a sign of inflammatory hyper-reactivity. In patients with type-2 diabetes and low-grade inflammation in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study, irbesartan 300 mg/day significantly reduced levels of hs-C-reactive protein compared with placebo (P < 0.001),42 and anti-inflammatory effects of ARBs have been documented in hypertensive patients with microinflammation.43

Taken together, our observations indicate no difference between the effects of ARBs and ACE-Is, not only on inflammatory markers but also on biomarkers of myocardial ischaemia, damage, and dysfunction, and biomarkers of endothelial dysfunction.

The blood pressure of the study participants did not change during treatment with either irbesartan or enalapril. This may be because patients did not have high blood pressure at baseline, blood pressure was already lowered by prior cardiovascular drug treatments, and, on admission, these patients were put at rest with the addition of intravenous nitrates and/or beta-blockers. The fact that many patients were discontinued from receiving the full treatment regimen during the study because of hypotension may also explain the absence of a visible effect on blood pressure.

To date, it has not been made clear whether there is a difference between angiotensin II type-1 (AT1) receptor inhibition and ACE inhibition with respect to reducing inflammatory and other cardiovascular markers, with very few studies, all of limited sample size, conducting direct comparisons. Schieffer et al.36 compared the effects of irbesartan 300 mg/day and enalapril 20 mg/day for 3 months on inflammatory markers in 48 patients with CAD, arterial hypertension, and low serum levels of low-density lipoprotein (<150 mg/dL) following coronary angioplasty. Whereas both treatments significantly reduced serum MMP-9 protein and MMP-9 activity, only irbesartan significantly reduced serum IL-6, hs-C-reactive protein, and platelet aggregation levels compared with baseline (P < 0.01), suggesting that AT1 receptor blockade may be more effective than ACE inhibition in these patients with moderate inflammatory activation.36 However, Rosei et al.,44 who studied a different set of inflammatory markers, found that candesartan and enalapril were similarly effective at reducing levels of circulating adhesion molecules and markers of endothelial dysfunction and inflammation in 129 patients with diabetes and hypertension. The ARCHIPELAGO study was adequately powered to compare the two drugs and found no difference between AT1 blockade and ACE inhibition in decreasing circulatory inflammatory factors, notably in a patient population with significant inflammatory levels. Our results are not surprising in the light of larger clinical endpoint head-to-head trials of ARBs and ACE-Is (Valsartan in Acute Myocardial Infarction Trial, VALIANT, and the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, ONTARGET),33,45 which showed similar clinical outcomes, with ARBs being equivalent to ACE-Is in reducing fatal or non-fatal cardiovascular events in high-risk patients with cardiovascular disease.

High plasma aldosterone levels on hospital admission are associated with early and late adverse clinical outcomes, including mortality in patients with acute MI.46 Results from previous studies in patients with acute MI suggested that very early initiation of RAAS blockade may be more beneficial than later treatment onset. In two major trials, Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL)32 and VALIANT,33 which compared the effects of ARBs and ACE-Is on mortality rates in high-risk patients following acute MI, treatment was started several days after the acute event (mean 3.5 days in OPTIMAAL; 5 days in VALIANT), and both studies failed to show a significant difference in survival between treatments. Post hoc analysis of the earlier, large-scale SMILE study showed that initiation of an ACE-I within 24 h of symptom onset in patients with acute MI significantly reduced the relative risk of death and severe congestive heart failure [0.60, 95% confidence interval (CI) 0.45–0.81; P < 0.05],31 suggesting that ACE-I treatment yielded greater benefits from very early initiation in patients with acute MI. It is not known whether patients with unstable angina or NSTEACS are able to derive a similar benefit from early treatment. Our results comparing early-to-late initiation of RAAS blockade in NSTEACS did not find a benefit on any of the cardiovascular biomarkers measured.

Conclusions

In the present study, over a 2 month period, irbesartan was no more effective than enalapril in decreasing plasma levels of markers of inflammation, endothelial dysfunction, myocardial ischaemia, necrosis or dysfunction, and left ventricular remodelling, all being well-known markers of risk in patients with ACS. There was no overall interaction between treatment and the timing of treatment initiation on the reduction of the biomarkers examined. Both treatments were well tolerated and did not differ in the prevention of further cardiovascular events. In the absence of side effects such as cough, because of their lower cost, ACE-Is should remain the preferred agent over ARBs in NSTEACS.

Funding

This study was funded by sanofi aventis and Bristol-Myers Squibb.

Conflict of interest: G.M. discloses the following relationships: research grants (directly to the institution)—Bristol Myers Squibb, sanofi aventis group, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération Française de Cardiologie; consulting fees—sanofi-aventis group, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, GlaxoSmithKline, The Medicines Company, and Schering-Plough. He has also received lecture fees from sanofi aventis, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, Cordis, GlaxoSmithKline, and Schering-Plough. D.L.B. discloses the following relationships: research grants (directly to the institution)—Bristol Myers Squibb, Cogentus, Eisai, Ethicon, Heartscape, sanofi aventis, The Medicines Company; honoraria (donated to non-profits for >2 years)—Astra Zeneca, Bristol Myers Squibb, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Paringenix, PDL, sanofi aventis, Schering Plough, The Medicines Company, TNS Healthcare; speaker's bureau (>2 years ago)—Bristol Myers Squibb, sanofi aventis, The Medicines Company; consultant/advisory board (donated to non-profits for >2 years)—Astellas, Astra Zeneca, Bristol Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, sanofi aventis, Schering Plough, Scios, Takeda, The Medicines Company, TNS Healthcare, Vertex; expert testimony regarding clopidogrel (>2 years ago; the compensation was donated to a non-profit organization). Cleveland Clinic Coordinating Center currently receives or has received research funding from Abraxis, Alexion Pharma, AstraZeneca, Atherogenics, Aventis, Biosense Webster, Biosite, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardionet, Centocor, Converge Medical Inc., Cordis, Dr. Reddy's, Edwards Lifesciences, Esperion, GE Medical, Genentech, Gilford, GSK, Guidant, Johnson & Johnson, Kensey-Nash, Lilly, Medtronic, Merck, Mytogen, Novartis, Novo Nordisk, Orphan Therapeutics, P&G Pharma, Pfizer, Roche, Sankyo, sanofi aventis, Schering-Plough, Scios, St. Jude Medical, Takeda, TMC, VasoGenix, Viacor.

Acknowledgements

This study was sponsored by sanofi aventis and Bristol-Myers Squibb. P. Milner, PhD, provided editorial assistance in the preparation of this manuscript. The authors take full responsibility for the content of this article.

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Author notes

ARCHIPELAGO: Acute coronary syndromes Randomized to a Controlled evaluation in the first Hours of presentation with Irbesartan vs. enalapril to Prevent Elevated inflammation, Limit myocardial ischemia And Generate better Outcome.

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