3.1. Study characteristics
We found 4338 potentially articles, among which 14 trials involving 11,624 individuals were included (Fig. 1).
Treatment duration ranged from 1 to 24 months (8.61 ± 5.77). Patients were randomized to spironolactone in 8 trials (n = 1412), eplerenone in 4 trials (n = 4081), canrenoate in 2 trials (n = 365) and assigned 1408, 3990, and 368 patients to control groups, respectively. The EPHESUS trial [12] accounted for more than half of the patients. Two studies [25, 13] did not use double-blind methods and one study [24] reported incomplete outcome data (Fig. 2).
The kappa statistic 0.83 (95% CI: 0.52 to 1.14) showed a good agreement between reviewers (Supplemental material 3). The Modified Jadad scores of trials varied from 5 to 7 points, indicating that this meta-analysis was a relatively high-quality report.
3.2. All-cause mortality
11 studies included 11,037 patients reported all-cause mortality. 532/5523 (9.63%) and 630/5514 (11.43%) were observed in treatment and control arms, respectively, with a general reduction of 16% (RR 0.84, 95% CI (0.76, 0.94), P = 0.002, I2 = 0%, Fig. 3).
In addition, reduction benefits of MRA were particularly evident in subgroups such as STEMI patients, treatment initiation within 3 days and (3,7) days (RR 0.62, 95% CI (0.42, 0.90), P = 0.01, I2 = 0%; RR 0.70, 95% CI (0.49, 1.00), P = 0.05, I2 = 0%; RR 0.71, 95% CI (0.59, 0.86), P = 0.0004, I2 = 0%, Fig. 4). Early administration of MRA within 7 days resulted in a significant reduction in death after randomization (RR 0.71, 95% CI (0.60, 0.84), P < 0.0001, I2 = 0%, Fig. 3).
The Begg’s test (P = 0.64) and the Egger’s test (P = 0.63) were observed, and funnel plot was symmetrical distribution, which represented a low publication bias (Fig. 5). None of the individual studies significantly influenced the pooled all-cause mortality estimates in the leave-one-out sensitivity.
3.3. New or worsening HF
8 RCTs involving 10,515 patients (10.74% in the MRA group vs 12.14% in the control group) showed a significant 14% reduction in new or worsening HF after MRA treatment (Fig. 3). The EPHESUS trial [12] provided weights of 81.1% for new or worsening HF. RR excluding it resulted in no statistical significance: from (0.86, p = 0.007) to (0.86, p = 0.23).
3.4. Cardiovascular and all-cause hospitalizations
MRA groups (n = 452/5294; n = 1493/3384) had a greater reduction than control arms (n = 537/5193; n = 1531/3376), but pooled data showed that MRA treatment was not associated with a reduced risk of cardiovascular or all-cause hospitalizations, respectively (Table 3).
Table 3. Other statistical results of mineralocorticord receptor antagonists use in post-AMI patients.
|
Heterogeneity
|
Outcomes
|
Trials
|
N
|
RR/ MD
|
95% CI
|
P value
|
I2 (%)
|
P value
|
Left ventricular ejection fraction
|
8
|
1707
|
2.96
|
(0.96, 4.96)
|
0.004
|
92
|
< 0.000
|
Left ventricula end-systolic daimeter (cm)
|
3
|
748
|
-0.19
|
(-0.53, 0.15)
|
0.26
|
94
|
< 0.000
|
Left ventricula end-diastolic daimeter (cm)
|
3
|
748
|
-0.13
|
(-0.26, -0.01)
|
0.04
|
64
|
0.06
|
Left ventricular end-diastolic volume index (ml/m2)
|
5
|
1046
|
-3.35
|
(-5.37, -1.34)
|
0.001
|
0
|
0.58
|
Left ventricular end-systolic volume index (ml/m2)
|
5
|
1070
|
-4.73
|
(-8.75, -0.70)
|
0.02
|
96
|
< 0.000
|
E/A ratio
|
3
|
907
|
0.12
|
(0.10, 0.14)
|
< 0.000
|
0
|
0.80
|
New or worsening HF
|
8
|
10515
|
0.86
|
(0.78, 0.96)
|
0.007
|
0
|
0.74
|
All-cause hospitalizations
|
3
|
6760
|
0.97
|
(0.92, 1.03)
|
0.31
|
29
|
0.24
|
Cardiovascular hospitalizations
|
3
|
7690
|
0.92
|
(0.83, 1.02)
|
0.10
|
31
|
0.23
|
Renal dysfunction
|
4
|
1534
|
0.45
|
(0.03, 6.63)
|
0.56
|
71
|
0.03
|
Hypokalemia
|
3
|
7702
|
0.42
|
(0.19, 0.95)
|
0.04
|
64
|
0.06
|
N = number; MD = mean difference; RR = relative ratio; CI= confidence interval; I2 = inconsistency index.
3.5. Changes of cardiac structure and function
MRA use improved LVEF with highly heterogeneous results (Table 3). In addition, improvement in left ventricular end-diastolic volume index (LVEDVI) and end-systolic volume index (LVESVI) was also apparent (Table 3), and further analysis demonstrated a reduction in left ventricula end-diastolic daimeter but not in left ventricula end-systolic daimeter under MRA treatment (Table 3). The ratio of mitral diaslotic early flow velocity E to mitral late flow velocity A (E/A) was improved by MRA treatment (Table 3). For LVEF, LVESVI, and LVEDVI, in patients without LVSD (MD 2.74, 95% CI (2.49, 2.99), P < 0.00001, I2 = 0%; MD −6.23, 95% CI (−10.93, −1.52), P = 0.009, I2 = 98%; MD −3.13, 95% CI (−5.79, −0.47), P = 0.02, I2 = 29%, Fig. 6), treated ≤ 6 months (MD 3.86, 95% CI (1.43, 6.29), P = 0.002, I2 = 93%; MD −5.39, 95% CI (−9.73, −1.04), P = 0.02, I2 = 97%; MD −3.41, 95% CI (−5.50, −1.32), P = 0.001, I2 = 0%, Fig. 7) subgroups, the statistical results were significant, respectively.
3.6. Safety
A higher rate of hyperkalemia was 4.79% in the MRA arms versus 2.80% in control groups. Gynecomastia occurred in experiment (0.64%) and control (0.30%) patients. Their overall incidence was nearly 2-fold higher than control groups (RR 1.73, 95% CI (1.44, 2.08), P < 0.00001, I2 = 42%, Fig. 8). Meanwhile, MRA use increased serum potassium and creatinine levels (MD 0.07 (mmol/l), 95% CI (0.02, 0.12), P = 0.004, I2 = 74%; MD 0.02 (mg/dl), 95% CI (−0.00, 0.04), P = 0.05, I2 = 73%, Fig. 8), but no corresponding increase in the incidence of renal dysfunction was found (Table 3). In contrast, hypokalemia occured less frequently in MRA groups (Table 3). Eplerenone (RR 1.48, 95% CI (1.21, 1.82), P = 0.0002, I2 = 0%), canrenate (RR 3.47, 95% CI (1.43, 8.42), P = 0.006, I2 = 29%), spironolactone (RR 10.33, 95% CI (2.85, 37.41), P = 0.0004, I2 = 0%) respectively increased the incidence of hyperkalemia.