European Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis - EUTOPIA
The goal of the trial was to evaluate the anti-inflammatory effects of the angiotensin II receptor antagonist olmesartan compared with placebo in patients with hypertension and microinflammation.
Patients Screened: 507
Patients Enrolled: 199
Mean Follow Up: 12 weeks
Mean Patient Age: Mean age 58 years
Age >18 years, essential hypertension, any diagnosed atherosclerotic disease, type 2 diabetes mellitus, and/or LDL between 3.89 and 6.48 mmol/l, DBP of 95-110 mm Hg at or at the end of the two-week taper-off period for patients already receiving antihypertensive treatment, hsCRP >3 mg/l, and detectable IL-6 and ICAM-1 serum levels
Any type of secondary hypertension; malignant hypertension; renovascular occlusive disease; renal transplant; serum creatinine ≥150 µmol/l and/or proteinuria ≥100 mg/dl; any other type of chronic inflammatory disease; an acute inflammatory disease and/or hsCRP >20 mg/l; ECG evidence of second- or third-degree atrioventricular block; cardiac arrhythmia requiring therapy; bradycardia; heart failure; myocardial infarction within six months; history or clinical evidence of significant cerebrovascular disease; malabsorption syndrome; and a history of any serious underlying disease; sitting DBP >110 mm Hg or sitting systolic blood pressure >200 mm Hg; statin use within three months; significantly elevated liver enzyme levels; or known hypersensitivity or contraindication to angiotensin II subtype 1 receptor antagonists, statins, hydrochlorothiazide, or related drugs
Anti-inflammatory markers (hsCRP, hsTNF-alpha), IL-6, ICAM-1, and MCP-1
Patients were randomized to treatment with olmesartan (20 mg; n=100) or placebo (n=99) for 12 weeks. At six weeks, patients in both arms were also treated with pravastatin (20 mg per day).
Patients with elevated blood pressure (diastolic blood pressure [DBP] ≥90 mm Hg) were treated with either 12.5 or 25 mg hydrochlorothiazide.
Baseline inflammatory markers were high in both the olmesartan and placebo groups: high-sensitivity C-reactive protein (hsCRP) 4.69 and 4.51 mg/l; high-sensitivity tumor necrosis factor-alpha (hsTNF-alpha) 4.63 and 4.13 pg/ml; interleukin-6 (IL-6) 3.56 and 3.62 pg/ml; and monocyte chemotactic protein-1 (MCP-1) 450 and 455 pg/ml, respectively.
At six-week follow-up (prior to the addition of pravastatin to the treatment regimen), inflammatory markers were significantly lower in the olmesartan arm compared to baseline, including hsCRP (-15.1%, p<0.05), hsTNF-alpha (-8.9%, p<0.02), IL-6 (-14.0%, p<0.05), and MCP-1 (-6.5%, p<0.01). There was no change from baseline in the inflammation markers in the placebo treatment arm. There were also no differences from baseline in either group in total cholesterol or low-density lipoprotein (LDL) cholesterol at six weeks.
After 12 weeks of therapy (including six weeks of treatment with pravastatin in both arms), inflammatory markers were significantly lower in the olmesartan plus pravastatin arm compared to baseline, including hsCRP (-21.1%, p<0.02), hsTNF-alpha (-13.6%, p<0.01), and IL-6 (-18.0%, p<0.01). There was no difference from baseline in inflammation markers in the pravastatin alone group (i.e., cotherapy with placebo). Pravastatin treatment was associated with a significant reduction in LDL in both the olmesartan and placebo treatment groups (-15.1% and -12.1%, respectively; both p<0.001). Intercellular adhesion molecule-1 (ICAM-1) levels did not differ significantly from baseline in either treatment group at either six weeks or 12 weeks.
Blood pressure was lowered in both groups, but the degree of reduction was greater in the olmesartan group. Additionally, fewer patients in the olmesartan group than the placebo group required additional treatment with hydrochlorothiazide to control blood pressure (21.0% vs. 42.4%).
Among patients with essential hypertension and microinflammation, treatment with the angiotensin II receptor antagonist olmesartan was associated with a reduction in inflammatory markers compared with placebo. However, addition of pravastatin after six weeks of placebo therapy was not associated with a reduction in inflammatory markers, but was associated with a reduction in LDL.
Elevated levels of CRP have been shown to be associated with increased risk of cardiovascular events. It is unknown if the reduction in hsCRP levels with the angiotensin II receptor antagonist olmesartan would lead to reductions in cardiovascular events.
Fliser D, Buchholz K, Haller H. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation 2004;110:1103-7.
Keywords: Angiotensin Receptor Antagonists, Inflammation, Follow-Up Studies, Cholesterol, LDL, Interleukin-6, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diabetes Mellitus, Type 2, Tumor Necrosis Factor-alpha, Tetrazoles, Lipoproteins, LDL, C-Reactive Protein, Imidazoles, Chemokine CCL2, Intercellular Adhesion Molecule-1, Pravastatin, Hydrochlorothiazide, Hypertension
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