Antihypertensive effect of the mineralocorticoid receptor antagonist eplerenone: a pooled analysis of patient-level data from comparative trials using regulatory-approved doses

Figures & data

Table 1 Overview of patient disposition

Type of studies	Patients randomized	Patients treated	Patients with post-baseline efficacy assessments	Patients receiving at least 6 weeks of fixed dose of study drug
Placebo-controlled studies	1,679	1,677	1,640	1,394
Active-controlled studies	1,517	1,515	1,469	1,304
Total	3,196	3,192	3,109	2,698

Notes: Placebo-controlled studies included 010, 015, 020, 023, 024, 049, and 403. Active-controlled studies included 010, 015, 016, 019, 020, 022, and 026.

Figure 1 Patient disposition. (A) Placebo-controlled studies. (B) Active-controlled studies.

Table 2 Baseline demographic and clinical characteristics of per-protocol seta

	Placebo-controlled studies			Active-controlled studies
	Placebo	Eplerenone 50 mg	Eplerenone 100 mg	Active	Eplerenone 50 mg	Eplerenone 100 mg
Total N	637	441	316	806	282	216
Age in years (SD)	54.9 (11.1)	55.2 (11.2)	53.3 (9.6)	56.7 (11.8)	55.3 (12.6)	54.4 (11.0)
Ethnicity (%)
Caucasian	55.4	62.6	52.5	75.7	79.1	72.7
Black	22.1	13.4	18.4	20.3	14.9	22.2
Asian	8.5	11.3	14.9	0.6	0.4	0.0
Hispanic	13.5	11.8	13.3	3.0	5.7	4.6
Other	0.5	0.9	0.9	0.4	0.0	0.5
Female gender (%)	50.1	48.1	44.6	48.3	49.3	47.2
BMI (kg/m^2)
Female	29.4 (5.9)	29.9 (5.9)	30.0 (6.4)	31.1 (6.7)	30.5 (5.6)	31.0 (6.2)
Male	29.2 (4.6)	29.4 (5.7)	28.7 (4.3)	29.3 (4.4)	29.2 (5.5)	29.7 (4.1)
Baseline blood pressure (mmHg)
Systolic	151.8 (12.0)	152.8 (13.0)	154.1 (13.7)	156.5 (14.4)	153.2 (14.0)	153.7 (14.4)
Diastolic	99.1 (3.9)	99.3 (4.2)	100.4 (4.6)	97.5 (7.1)	98.3 (5.5)	98.8 (5.6)
Heart rate (bpm)	72.7 (9.3)	72.6 (8.9)	73.2 (8.8)	72.5 (9.4)	73.5 (9.6)	72.9 (8.6)
eGFRb in mL/min/1.73 m^2 (SD)	100.5 (11.5)	98.8 (10.1)	101.0 (9.7)	99.1 (11.7)	99.1 (11.3)	100.9 (11.0)
Potassium (mmol/L)	4.3 (0.4)	4.2 (0.4)	4.2 (0.4)	4.2 (0.4)	4.2 (0.3)	4.2 (0.4)
History of cardiovascular diseasec (%)	11.6	12.5	14.6	20.1	19.5	17.6
Diabetesd (%)	7.8	5.2	6.6	10.2	6.0	4.2

Notes:

a Values are means (± SD) unless otherwise stated.

b Transformed data using the CKD-EPI for estimation of glomerular filtration rate.

c Major cardiovascular exclusion criteria from participation in the clinical trials included recent history of MI/acute coronary syndrome, intermittent claudication, cerebrovascular disease, severe valvular disease, NYHA classification II–IV chronic heart failure.

d Patients with Type I and Type II diabetes were excluded from studies 010 and 403; patients with Type I and uncontrolled Type II diabetes were excluded from studies 016, 019, 020, 022, 023, 024, 026 and 049; patients with uncontrolled Type I and Type II diabetes were excluded from study 015.

Abbreviations: BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; NYHA, New York Heart Association.

Table 3 Change from baseline in seated SBP/DBP

Placebo-controlled studies
	Placebo	Eplerenone 50 mg daily	Eplerenone 100 mg daily	Eplerenone 50 mg vs placebo	Eplerenone 100 mg vs placebo
Mean change from baseline in BPa (SBP/DBP)	−4.98/−5.67	−12.53/−9.72	−13.73/−9.96	−7.55/−4.05	−8.75/−4.30
95% CI for SBP	−6.03, −3.93	−13.73, −11.33	−15.22, −12.24	−9.14, −5.96	−10.57, −6.93
95% CI for DBP	−6.30, −5.03	−10.44, −8.99	−10.86, −9.06	−5.01, −3.09	−5.39, −3.20
P-value				<0.0001/<0.0001	<0.0001/<0.0001
Active-controlled studies
	Active treatment	Eplerenone 50 mg daily	Eplerenone 100 mg daily	Eplerenone 50 mg vs active	Eplerenone 100 mg vs active
Mean change from baseline in BPa	−13.28/−9.31	−16.53/−11.21	−17.58/−10.77	−3.25/−1.90	−4.30/−1.46
95% CI for SBP	−14.29, −12.27	−18.27, −14.79	−19.58, −15.58	−5.25, −1.25	−6.56, −2.03
95% CI for DBP	−9.91, −8.71	−12.25, −10.17	−11.96, −9.59	−3.09, −0.71	−2.81, −0.12
P-value				0.0015/0.0018	0.0002/0.0328

Note:

a Pooled least-square means and 95% CI based on a meta-analysis fixed-effects model with factors for study, treatment group, and baseline covariate.

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

Table 4 Treatment-emergent adverse events

Placebo-controlled studies
	Placebo	Eplerenone 50 mg daily	Eplerenone 100 mg daily
N	729	512	436
No. of patients with serious AEs (%)	10 (1.4)	10 (2.0)	2 (0.5)
No. of patients who discontinued due to AEs (%)	15 (2.1)	22 (4.3)	7 (1.6)
No. of patients who discontinued due to serious AEs (%)	2 (0.3)	6 (1.2)	1 (0.2)
AEs, no. of events (%)a
Arthralgia	8 (1.1)	13 (2.5)	14 (3.2)
Dizziness	26 (3.6)	21 (4.1)	23 (5.3)
Headache	132 (18.1)	78 (15.2)	75 (17.2)
Diarrhea	22 (3.0)	11 (2.1)	9 (2.1)
Nausea	20 (2.7)	22 (4.3)	14 (3.2)
Hypercholesterolemia	3 (0.4)	6 (1.2)	14 (3.2)
Sinusitis	15 (2.1)	13 (2.5)	17 (3.9)
Upper respiratory tract infection	40 (5.5)	32 (6.3)	38 (8.7)
Bronchitis	12 (1.6)	8 (1.6)	13 (3.0)
Edema peripheral	23 (3.2)	13 (2.5)	9 (2.1)
Fatigue	18 (2.5)	14 (2.7)	14 (3.2)
Active-controlled studies
	Active	Eplerenone 50 mg daily	Eplerenone 100 mg daily
N	892	349	274
No. of patients with serious AEs (%)	24 (2.7)	15 (4.3)	5 (1.8)
No. of patients who discontinued due to AEs (%)	71 (8.0)	35 (10.0)	15 (5.5)
No. of patients who discontinued due to serious AEs (%)	11 (1.2)	8 (2.3)	1 (0.4)
AE, no. of events (%)a
Dizziness	45 (5.0)	16 (4.6)	14 (5.1)
Headache	151 (16.9)	42 (12.0)	58 (21.2)
Diarrhea	33 (3.7)	10 (2.9)	4 (1.5)
Nausea	30 (3.4)	12 (3.4)	11 (4.0)
Hypercholesterolemia	6 (0.7)	6 (1.7)	9 (3.3)
Hyperglycemia	22 (2.5)	5 (1.4)	2 (0.7)
Creatine phosphokinase increased	28 (3.1)	8 (2.3)	9 (3.3)
Coughing	27 (3.0)	8 (2.3)	5 (1.8)
Sinusitis	22 (2.5)	7 (2.0)	16 (5.8)
Upper respiratory tract infection	81 (9.1)	24 (6.9)	24 (8.8)
Bronchitis	23 (2.6)	5 (1.4)	9 (3.3)

Note:

a AEs (WHO-ART dictionary Preferred Terms) occurring in at least 3% of patients in any group.

Abbreviations: AEs, adverse events; WHO-ART, World Health Organization Adverse Reaction Terminology.

Figure 2 Change from baseline in seated SBP/DBP: (A) placebo-controlled studies and (B) active-controlled studies.

Notes: LS Means model includes Study, Treatment, and Baseline BP. The per-protocol analysis set included all patients who were randomly assigned to treatment (eplerenone 50 mg daily, eplerenone 100 mg daily, or active control), who had a baseline primary efficacy evaluation, took at least one dose of study drug, and received at least 6 weeks of fixed dose of study drug. Weight of blue symbol is defined as percentage study contribution to total pooled results. Study 015 is not represented in the eplerenone 100 mg analysis due to lack of treatment arm with that dosage. Study 019 is not represented in the eplerenone 50mg analysis due to lack of treatment arm with that dosage. See Table 3 for the 95% confidence intervals of differences in seated SBP/DBP between eplerenone and placebo.

Table 5 Potassium laboratory values

Placebo-controlled studies
	Placebo	Eplerenone 50 mg daily	Eplerenone 100 mg daily
N	715	489	430
Change from baseline in serum potassium (mean ± SE)	0.00 (0.013)	0.13 (0.017)	0.13 (0.018)
No. of patients with K+ <3.5 mmol/L (%)	22 (3.1)	5 (1.0)	5 (1.2)
No. of patients with K+ >5.5 mmol/L (%)	6 (0.8)	6 (1.2)	6 (1.2)
No. of patients with K+ >6.0 mmol/L (%)	3 (0.4)	0 0.0	1 (0.2)
No. of patients with hypokalemia reported as an adverse event by the investigators (%)	2 (0.3)	1 (0.2)	2 (0.5)
No. of patients with hyperkalemia reported as an adverse event by the investigators (%)	3 (0.4)	7 (1.4)	2 (0.5)
No. of diabetic patients with K+ <3.5 mmol/L (%)	0/57 (0.0)	0/26 (0.0)	0/30 (0.0)
No. of diabetic patients with K+ >5.5 mmol/L (%)	1/57 (1.8)	1/26 (3.8)	0/30 (0.0)
No. of diabetic patients with K+ >6.0 mmol/L (%)	0/57 (0.0)	0/26 (0.0)	0/30 (0.0)
Active-controlled studies
	Active	Eplerenone 50 mg daily	Eplerenone 100 mg daily
N	876	322	266
Change from baseline in serum potassium (mean ± SE)	0.00 (0.013)	0.09 (0.020)	0.11 (0.024)
No. of patients with K+ <3.5 mmol/L (%)	57 (6.5)	5 (1.6)	4 (1.5)
No. of patients with K+ >5.5 mmol/L (%)	14 (1.6)	6 (1.9)	5 (1.9)
No. of patients with K+ >6.0 mmol/L (%)	1 (0.1)	0 (0.0)	1 (0.4)
No. of patients with hypokalemia reported as an adverse event by the investigators (%)	8 (0.9)	1 (0.3)	2 (0.7)
No. of patients with hyperkalemia reported as an adverse event by the investigators (%)	3 (0.3)	1 (0.3)	4 (1.5)
No. of diabetic patients with K+ <3.5 mmol/L (%)	4/85 (4.7)	0/20 (0.0)	0/10 (0.0)
No. of diabetic patients with K+ >5.5 mmol/L (%)	1/85 (1.2)	2/20 (10.0)	0/10 (0.0)
No. of diabetic patients with K+ >6.0 mmol/L (%)	0/85 (0.0)	0/20 (0.0)	0/10 (0.0)

Table S1 Adequate and well-controlled studies included in pooled analysis

Study grouping	Study number	Eplerenone dosea	Placebo control	Active control (doses)	Coadministration	Dosing protocol	Double-blind treatment duration	Key blood pressure inclusion criteria
Placebo-controlled, fixed-dose monotherapy	010^Citation1	50, 100, 400 mg QD 25, 50, 200 mg BID	X	Spironolactone (50 mg BID)		Fixed dose (dose ranging)	8 weeks	Sitting DBP of ≥95 mmHg and <114 m
	049^Citation2	25, 50, 100, 200 mg	X			Fixed dose (dose ranging)	12 weeks	Sitting DBP ≥95 mmHg and <110 mmHg and untreated mean sitting SBP <180 mmHg
	403^Citation3	50, 100, 200 mg QD	X			Fixed dose (dose ranging)	8 weeks	Sitting DBP ≥95 mmHg and <115 mmHg
	015 (Pfizer Inc. Data on file [E3- 01-06-015 August 23, 2001])	25, 50, 200 mg	X	HCTZ (12.5, 25 mg)	HCTZ	Fixed dose (factorial design)	8 weeks	Sitting DBP of ≥95 mmHg and <110 mmHg
Placebo-controlled, titration-to-effect monotherapy	020^Citation4	50, 100, 200 mg	X	Losartan (50, 100 mg)		Titration-to- effect	16 weeks	Sitting DBP ≥95 mmHg and <110 mmHg and a mean sitting SBP <180 mmHg
Placebo-controlled coadministration with other antihypertensives	023^Citation5	50, 100 mg	X		ACE-I or A-II antagonist	Titration-to- effect	8 weeks	Sitting DBP ≥95 mmHg and <110 mmHg and a mean sitting SBP <180 mmHg
	024 (Pfizer Inc. Data on file [IE3- 99-02-024, October 10, 2001])	50, 100 mg	X		BB or CCB	Titration-to- effect	8 weeks	Sitting DBP ≥95 mmHg and <110 mmHg and a mean sitting SBP <180 mmHg
Active-controlled, fixed-dose monotherapy	010^Citation1	50, 100, 400 mg QD 25, 50, 200 mg BID	X	Spironolactone (50 mg BID)		Fixed dose (dose ranging)	8 weeks	Sitting DBP of 95 mmHg and ≤114 mmHg
	015 (Pfizer Inc. Data on file [E3- 01-06-015 August 23, 2001])	25, 50, 200 mg	X	HCTZ (12.5, 25 mg)	HCTZ	Fixed dose (factorial design)	8 weeks	Sitting DBP of ≥95 mmHg and <110 mmHg
Active-controlled, titration-to-effect monotherapy	020^Citation4	50, 100, 200 mg	X	Losartan (50, 100 mg)		Titration-to- effect	16 weeks	Sitting DBP ≥95 mmHg and <110 mmHg and a mean sitting SBP <180 mmHg
Active-controlled, monotherapy, without placebo	019^Citation6	100, 200 mg		Losartan (50, 100 mg)		Titration-to- effect	16 weeks	Sitting DBP ≥90 mmHg and <115 mmHg and a mean SBP <200 mmHg
	016^Citation7	25, 50, 100, 200 mg		Enalapril (5, 10, 20, 40 mg)		Titration-to- effect	12 months	Sitting DBP ≥95 mmHg and <110 mmHg and a mean sitting SBP <190 mmHg
	022^Citation8	50, 100, 200 mg		Amlodipine (2.5, 5, 10 mg)		Titration-to- effect	24 weeks	Sitting SBP ≥150 mmHg and <165 mmHg, and PP ≥70 mmHg or Sitting SBP ≥165 mmHg and <200 mmHg, and DBP <95 mmHg
	026 (Pfizer Inc. Data on file [IE3–99–02–026, October 21, 2001])	50, 100, 200 mg		Amlodipine (2.5, 5, 10 mg)		Titration-to- effect	16 weeks	Sitting DBP ≥95 mmHg and <110 mmHg and a mean sitting SBP <180 mmHg

Note:

a All regimens were QD unless otherwise noted.

Abbreviations: A-II antagonist, angiotensin II antagonist; ACE-I, angiotensin-converting enzyme inhibitor; BB, beta blocker; CCB, calcium-channel blocker; DBP, diastolic BP; HCTZ, hydrochlorothiazide; PP, pulse pressure; SBP, systolic BP.

Table S2 Other controlled studies not included in pooled analysis

Study grouping	Study	Eplerenone doses	Active control doses	Open-label additional antihypertensives	Dosing protocol	Double-blind treatment duration	Reason for not including in pooled analysis
Secondary hypertension due to primary hyperaldosteronism	018^Citation9	100, 200, 300 mg		Spironolactone (75, 150, 225 mg)		Titration-to-effect 16 weeks	Study population outside approved indication
Target organ damage	017^Citation10	50→100→ 200 mg QD	Enalapril (10→20→40 mg QD) OR Enalapril 10 mg QD with eplerenone 50 mg →100 mg →200 mg QD	HCTZ, amlodipine	Forced up-titration	9 months	Study conducted in hypertensive patients with left ventricular hypertrophia, a subpopulation not included in label
	021 (Pfizer Inc. Data on file [IE3-99-02-021, October 19, 2001])	50→100→ 200 mg QD	Enalapril (10→20→40 mg QD) OR Enalapril 10 mg QD with eplerenone 50 mg →100 mg →200 mg QD	HCTZ, amlodipine	Forced up-titration	24 weeks	Study conducted in hypertensive patients with MAU, a subpopulation contraindicated in label
	067^Citation11	50, 100 mg QD	Enalapril (20 mg QD) OR Enalapril 20 mg QD with either eplerenone 50 mg QD, or 100 mg QD	Amlodipine	Fixed dose	12 weeks	Study conducted in hypertensive patients with MAU, a subpopulation contraindicated in label

Abbreviations: HCTZ, hydrochlorothiazide; MAU, microalbuminuria.

Table S3 Uncontrolled studies not included in pooled analysis

Study grouping	Study	Dosea	Placebo control	Active control (doses)	Coadministration	Dosing protocol	Treatment duration	Reason for not including in pooled analysis
Open-label, safety	025^Citation12	50, 100, 200 mg	None	None	Various antihypertensives (if BP uncontrolled with 200-mg dose)	Titration-to-effect	14 months	Not a controlled study
	061 (Pfizer Inc. Data on file [JE3-01-02-061 –09 June 2005])	50, 100, 200 mg	None	None	Various antihypertensives (if BP uncontrolled with 200-mg dose)	Titration-to-effect	12 months	Not a controlled study

Note:

a All regimens were QD.

Abbreviation: BP: blood pressure.

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