Efficacy and Safety of Eplerenone, Enalapril, and Eplerenone/Enalapril Combination Therapy in Patients With Left Ventricular Hypertrophy - 4E


The goal of the trial was to assess the relative efficacy of treatment with either eplerenone, an aldosterone antagonist, or the angiotensin-converting enzyme inhibitor enalapril in patients with mild-to-moderate hypertension and left ventricular hypertrophy (LVH).

Study Design

Study Design:

Patients Enrolled: 202
Mean Follow Up: 9 months
Mean Patient Age: mean age 59 years
Female: 38%

Patient Populations:

LVH diagnosed by either ECG or echocardiogram, had a history of hypertension (DBP <110 mm Hg and seated SBP ≤180 mm Hg if presently treated with antihypertensive medications or DBP 90-114 mm Hg and SBP 141-200 mm Hg if not presently treated), and were predominantly in sinus rhythm


Orthostatic hypotension; use of guanethidine, spironolactone, or reserpine in the prior 30 days; serum potassium level <3.0 or >5.0 mEq/l; serum creatinine level >1.5 mg/dl for men and >1.3 mg/dl for women; contraindication to MRI; LV ejection fraction <40% on echocardiogram; New York Heart Association class III to IV congestive heart failure or unstable angina; a history in the prior six months of Q-wave MI, stroke, transient ischemic attack, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft; secondary hypertension; contraindication or hypersensitivity to any study medication; type 1 or uncontrolled type 2 diabetes mellitus; acute or chronic hepatic disease; impaired renal function; drug or alcohol abuse problems; terminal illness; or the use of an investigational drug in the prior 30 days

Primary Endpoints:

Change from baseline in LV mass by MRI was the primary endpoint.

Secondary Endpoints:

Change from baseline in BP, urinary albumin excretion, and renin-angiotensin-aldosterone system (RAAS) hormones

Drug/Procedures Used:

Following a 14-day placebo run-in phase, 202 hypertensive patients with evidence of LVH were randomized to treatment with one of three therapies: eplerenone (200 mg; n=64), enalapril (40 mg; n=71), or a combination of eplerenone and enalapril (200 mg/10 mg; n=67), and followed for nine months.

The study protocol included the capacity to add therapy with either a diuretic, hydrochlorothiazide (12.5-25 mg), or amlodipine (10 mg), if the blood pressure (BP) was not reduced effectively at eight weeks (diastolic BP [DBP] >90 mm Hg or systolic BP [SBP] >180 mm Hg).

LVH by magnetic resonance imaging (MRI) was the primary endpoint. A total of 153 patients completed both a baseline and nine-month follow-up MRI.

Principal Findings:

Among the 202 patients randomized, 153 had baseline and follow-up MRI and met the treatment criteria. LV mass was reduced by 14.5 g in the eplerenone arm (p<0.001 vs. baseline), by 19.7 g in the enalapril arm (p<0.001 vs. baseline), and by 27.2 g in the combination arm. The reduction in LV mass was not statistically different comparing the eplerenone arm versus the enalapril arm (p=0.258), but the reduction in the combination arm was significantly larger than eplerenone alone (p=0.007) and trended to be larger than enalapril (p=0.107).

SBP/DBP was lowered by 23.8/11.9 mm Hg in the eplerenone arm, 24.7/13.4 mm Hg in the enalapril arm, and by 28.7/14.4 mm Hg in the combination arm. SBP was reduced significantly more with eplerenone/enalapril than with eplerenone (p=0.048). All strategies decreased the urinary albumin-creatinine ratio significantly (UCAR); however, the reduction was significantly larger in the combination arm (52.6%) than either eplerenone alone (24.9%; p=0.001) or enalapril (37.4%; p=0.038) alone.

The only significant side effect was an increased incidence of cough among patients treated with enalapril. Additional therapy with other antihypertensives was required significantly more often among patients treated with enalapril (59%) compared with those treated with eplerenone (30%) or with the combination of the two agents (20%).


Among patients with mild-to-moderate hypertension and LVH, treatment with either eplerenone or enalapril or both was associated with a significant reduction in LV mass. The magnitude of the reduction in LV mass did not differ between the two agents, but was greater with the combination of the two agents. As might be anticipated, treatment with enalapril was associated with a cough. A large percentage of patients, especially in the enalapril arm, required add-on medication to achieve BP control.

LV mass on MRI is a surrogate endpoint, and its relation to clinical endpoints such as stroke, myocardial infarction (MI), and mortality remains to be fully defined. Given the small sample size, the trial was not adequately powered to detect a difference in death, MI, or stroke.


Pitt B, Reichek N, Willenbrock R, et al. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E–left ventricular hypertrophy study. Circulation 2003;108:1831-8.

Clinical Topics: Noninvasive Imaging, Prevention, Statins, Magnetic Resonance Imaging, Hypertension

Keywords: Hypertrophy, Left Ventricular, Myocardial Infarction, Stroke, Enalapril, Mineralocorticoid Receptor Antagonists, Diuretics, Blood Pressure, Creatinine, Spironolactone, Magnetic Resonance Imaging, Hydrochlorothiazide, Amlodipine, Cough, Hypertension

< Back to Listings