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 - ARCHIPELAGO

Description:

The goal of the trial was to evaluate treatment with irbesartan compared with enalapril (and early versus late treatment) among patients with non-ST-elevation acute coronary syndromes (NSTE-ACS).

Hypothesis:

Irbesartan would be more effective in reducing high-sensitivity C-reactive protein (hs-CRP) and other markers of inflammation and endothelial dysfunction.

Study Design

  • Randomized
  • Parallel
  • Blinded

Patients Screened: 440
Patients Enrolled: 417
Mean Follow Up: 2 months
Mean Patient Age: 67 to 77 years
Female: 26

Patient Populations:

  • Patients at least 18 years of age who were hospitalized for an NSTE-ACS
  • Symptom onset in the last 48 hours

Exclusions:

  • STEMI
  • Coronary angiography planned before sampling of inflammatory markers
  • Renal insufficiency
  • Serum potassium >5.5 mmol/L
  • Congestive heart failure
  • Angioplasty, surgery, or trauma in the last 3 months
  • Systolic blood pressure <100 mm Hg
  • Fever or concomitant infection
  • Chronic inflammatory disease or use of steroids
  • Use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker in the last 3 days
  • Investigational drug use in the last month

Primary Endpoints:

  • Change in hs-CRP

Secondary Endpoints:

  • Change in IL-6, sCD40L, sPLA2, MMP-9, MPO, BNP, troponin I, ischemia-modified albumin, microalbuminuria, and aldosterone
  • Change in blood pressure

Drug/Procedures Used:

Patients with NSTE-ACS were randomized to irbesartan 150 mg daily, titrated to 300 mg daily (n = 212) versus enalapril 10 mg daily, titrated to 20 mg daily (n = 217). By factorial design, patients were also randomized to begin study medications at hospital presentation versus hospital discharge.

Concomitant Medications:

At baseline, the use of antiplatelet medications was 53%, lipid-lowering medications 41%, and heparin 49%.

Principal Findings:

Overall, 417 patients were randomized. There was no difference in baseline characteristics between the groups. In the early irbesartan group, the mean age was 62 years, 24% were women, 14% were diabetics, and 48% had ST-segment depressions on electrocardiogram. At follow-up, blood pressure was 128/76 mm Hg in the irbesartan group versus 130/76 mm Hg in the enalapril group.

Over the 60-day follow-up period, the mean absolute change in hs-CRP was -8.7 in the irbesartan group versus -7.1 mg/dl in the enalapril group (p = 0.58). The mean reduction in hs-CRP from early initiation of irbesartan was -11.7 versus -5.7 mg/dl from late initiation. The mean reduction in hs-CRP from early initiation of enalapril was -7.3 versus -6.9 mg/dl from late initiation. There was no significant interaction between treatment and timing of study medications (p = 0.16).

The change in interleukin-6 (IL-6) (pg/ml) was -8.6 versus -7.5, matrix metalloproteinase-9 (MMP-9) (ng/ml) was -17.6 versus -18.6, myeloperoxidase (MPO) (ng/ml) was -16.6 versus -14.9, secretory non-pancreatic type II phospholipase A2 (sPLA2) (ng/ml) was -2.70 versus -2.47, soluble CD40 ligand (sCD40L) (ng/ml) was 2.0 versus 2.0, troponin I (ng/ml) was -2.7 versus -3.2, and B-type natriuretic peptide (BNP) (pg/ml) was -27.9 versus -48.0, respectively, for irbesartan versus enalapril (p > 0.05 for all comparisions). The number of major adverse cardiac events was similar between the groups: 20 versus 15, respectively.

Interpretation:

Among patients with an NSTE-ACS, the use of irbesartan was not superior to enalapril at 2 months of follow-up. Irbesartan or enalapril resulted in the same reduction of many markers of inflammation at follow-up, including hs-CRP. There was also no difference in markers of endothelial dysfunction or myocardial ischemia/damage.

Although there was a numerically greater reduction in inflammatory markers from early initiation of study medications, this difference was not significant. Both agents were well tolerated and associated with similar incidence of major adverse cardiac events.

References:

Montalescot G, Drexler H, Gallo R, Pearson T, Thoenes M, Bhatt DL. Effect of irbesartan and enalapril in non-ST elevation acute coronary syndrome: results of the randomized, double-blind ARCHIPELAGO study. Eur Heart J 2009;Aug 21:[Epub ahead of print].

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Heart Failure and Cardiac Biomarkers

Keywords: Depression, Inflammation, Coronary Artery Disease, Acute Coronary Syndrome, Enalapril, Interleukin-6, Blood Pressure, Electrocardiography, Tetrazoles, Biphenyl Compounds, Phospholipases A2, C-Reactive Protein, Troponin I, Peroxidase, Matrix Metalloproteinase 9, Diabetes Mellitus, Natriuretic Peptide, Brain, CD40 Ligand


< Back to Listings