Table 3.
Subgroup Analysis of Effects of ARNI on LV Indices According to Characteristics
| Subgroup | No. of Studies | n | NYHA Function Classification | 6MWD, m | LVEF, % |
|---|---|---|---|---|---|
| Age, y | |||||
| <65 | 8 | 9023 | −0.31 (−0.49, −0.12) I2=6%, Z=3.17 (P=0.002) | 15.04 (0.36, 29.72) I2=72%, Z=2.01 (P=0.04) | 4.27 (2.60, 5.93) I2=52%, Z=5.03 (P<0.00001) |
| ≥65 | 9 | 988 | −0.63 (−0.70, −0.57) I2=97%, Z=18.15 (P<0.00001) | 58.41 (34.57, 82.25) I2=0, Z=4.8 (P<0.00001) | 4.26 (3.51, 5.00) I2=73%, Z=11.19 (P<0.00001) |
| Region | |||||
| Europe | 14 | 1226 | −0.84 (−0.92, −0.76) I2=86%, Z=20.09 (P<0.00001) | 27.92 (15.68, 40.16) I2=63%, Z=4.47 (P<0.00001) | 5.03 (4.18, 5.88) I2=0, Z=11.62 (P<0.00001) |
| North America | 3 | 131 | −0.2 (−0.48, 0.08)*, Z=1.42 (P=0.15) | 23 (−25.26, 71.26)*, Z=0.93 (P=0.35) | 5.05 (3.05, 7.04) I2=59%, Z=4.96 (P<0.00001) |
| Asia | 1 | 118 | NR | NR | 2.8 (−0.16, 5.76)*, Z=1.86 (P=0.06) |
| Global multiple centers | 2 | 8700 | −0.2 (−0.31, −0.09)*, Z=3.52 (P=0.0004) | NR | 1.82 (0.41, 3.23) I2=18%, Z=2.53 (P=0.01) |
| Follow‐up | |||||
| Intervention effect ≤6 mo | 13 | 1009 | −0.76 (−0.85, −0.67) I2=91%, Z=17.00 (P<0.00001) | 23.77 (11.12, 36.42) I2=53%, Z=3.68 (P=0.0002) | 4.51 (3.77, 5.25) I2=68%, Z=11.9 (P<0.00001) |
| Intervention effect ≥9 mo | 7 | 9166 | −0.40 (−0.49, −0.30) I2=96%, Z=8.31 (P<0.00001) | 55.68 (21.53, 89.83),* Z=3.20 (P=0.001) | 2.96 (1.45, 4.46) I2=0, Z=3.86 (P=0.0001) |
| Dosage of ARNI | |||||
| Medium/high dose ≤50% | 7 | 386 | −1.1 (−1.31, −0.89)*, Z=10.31 (P<0.00001) | 24.15 (10.65, 37.64) I2=74%, Z=3.51 (P=0.0005) | 5.38 (4.44, 6.32) I2=0, Z=11.17 (P<0.00001) |
| Medium/high dose >50% | 11 | 9671 | −0.24 (−0.33, −0.15) I2=0, Z=5.17 (P<0.00001) | 45.4 (16.36, 74.45) I2=0, Z=3.06 (P=0.002) | 3.76 (2.61, 4.9) I2=35%, Z=6.43 (P<0.00001) |
| Mean baseline SBP | |||||
| SBP ≤120 mm Hg | 4 | 423 | −0.4 (−0.6, −0.2) I2=0, Z=3.85 (P=0.0001) | 44 (10.81, 77.19)*, Z=2.6 (P=0.009) | 3.73 (1.95, 5.5) I2=0, Z=4.11 (P<0.0001) |
| SBP >120 mm Hg | 8 | 9324 | −0.64 (−0.71, −0.57) I2=97%, Z=18 (P<0.00001) | 55.65 (29.31, 82.16) I2=0, Z=4.11 (P<0.0001) | 4.92 (4.05, 5.79) I2=62%, Z=11.08 (P<0.00001) |
| Different control groups | |||||
| ACEIs | 2 | 8649 | NR | NR | NR |
| ARBs | 3 | 533 | NR | NR | 2.73 (1.02, 4.45) I2=0, Z=3.13 (P=0.002) |
| Etiology | |||||
| Ischemic heart disease ≤50% | 6 | 310 | −0.35 (−0.64, −0.07) I2=0, Z=2.42 (P=0.02) | 57.58 (24.09, 91.06) I2=0, Z=3.37 (P=0.0008) | 3.86 (2.15, 5.57) I2=0, Z=4.43 (P<0.00001) |
| Ischemic heart disease >50% | 8 | 9194 | −0.8 (−0.96, −0.79) I2=89%, Z=20.23 (P<0.00001) | 23.35 (10.20, 36.49) I2=70%, Z=3.48 (P=0.0005) | 5.13 (4.24, 6.02) I2=1%, Z=11.29 (P<0.00001) |
| Concomitant therapy | |||||
| MRA ≤50% | 3 | 484 | −0.4 (−0.5, −0.3) I2=98%, Z=7.95 (P<0.00001) | 55.68 (21.53, 89.83),* Z=3.20 (P=0.001) | 2.73 (1.02, 4.45) I2=0, Z=3.13 (P=0.002) |
| MRA >50% | 12 | 9341 | −0.73 (−0.82, −0.65) I2=90%, Z=17.04 (P<0.00001) | 23.77 (11.12, 36.42) I2=53%, Z=3.68 (P=0.0002) | 5.04 (4.25, 5.82) I2=9%, Z=12.64 (P<0.00001) |
| Subgroup | No. of Studies | n | LVESV, mL | LVEDV, mL | LVESD, mm | LVEDD, mm | LVMI, g/m2 | LAV, mL | NT‐proBNP, pg/mL | sST2, ng/mL |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, y | ||||||||||
| <65 | 8 | 9023 | −17.06 (−31.04, −3.08) I2=0, Z=2.39 (P=0.02) | −18.39 (−34.87, −1.91) I2=0, Z=2.19 (P=0.03) | −3.30 (−6.78, 0.18)*, Z=1.86 (P=0.06) | −2.48 (−3.77, −1.18) I2=0, Z=3.74 (P=0.0002) | −6.59 (−11.23, −1.95) I2=0, Z=2.78 (P=0.005) | −7.32 (−14.35, −0.28) I2=0, Z=2.04 (P=0.04) | −474.47 (−538.92, −410.02) I2=0, Z=14.43 (P<0.00001) | −2.35 (−2.87, −1.83) I2=0, Z=8.86 (P<0.00001) |
| ≥65 | 9 | 988 | −5.52 (−8.42, −2.63) I2=40%, Z=3.73 (P=0.0002) | −18.07 (−20.50, −15.64) I2=87%, Z=14.60 (P<0.00001) | −3.40 (−6.54, −0.26)*, Z=2.12 (P=0.03) | −2.42 (−3.17, −1.67) I2=0, Z=6.35 (P<0.00001) | −4.35 (−7.93, −0.77)I2=73%, Z=2.38 (P=0.02) | −3.86 (−8.2, 0.48) I2=0, Z=1.75 (P=0.08) | −228.49 (−257.90, −199.09) I2=91%, Z=15.23 (P<0.00001) | −1.98 (−5.03, 1.08) I2=0, Z=1.27 (P=0.2) |
| Region | ||||||||||
| Europe | 14 | 1226 | −17.47 (−29.12, −5.82) I2=0, Z=2.94 (P=0.003) | −21.58 (−24.34, −18.83) I2=16%, Z=15.34 (P<0.00001) | NR | −2.41 (−3.21, −1.61) I2=0, Z=5.91 (P<0.00001) | NR | −6.72 (−13.94, 0.5)*, Z=1.82 (P=0.07) | −228.49 (−257.90, −199.09) I2=91%, Z=15.23 (P<0.00001) | −5.52 (−12.16, 1.12) I2=0, Z=1.63 (P=0.1) |
| North America | 3 | 131 | −21.87 (−44.39, 0.66) I2=0, Z=1.90 (P=0.06) | −22.17 (−47.37, 3.03) I2=0, Z=1.72 (P=0.08) | −3.60 (−6.16, −1.05) I2=0, Z=2.77 (P=0.006) | −2.48 (−3.63, −1.34) I2=0, Z=4.25 (P<0.0001) | NR | −9 (−25.07, 7.07)*, Z=1.1 (P=0.27) | NR | NR |
| Asia | 1 | 118 | −17.7 (−36.15, 0.75)*, Z=1.88 (P=0.06) | −22 (−44.25, 0.25)*, Z=1.94 (P=0.05) | −3.30 (−6.78, 0.18)*, Z=1.86 (P=0.06) | −2.20 (−5.04, 0.64)*, Z=1.52 (P=0.13) | NR | −18.30 (−49.32, 12.72)*, Z=1.16 (P=0.25) | NR | NR |
| Global multiple centers | 2 | 8700 | −6.9 (−11.35, −2.45)*, Z=3.04 (P=0.002) | −10.4 (−17.86, −2.94)*, Z=2.73 (P=0.006) | NR | NR | NR | NR | −305.95 (−346.51, −265.38) I2=94%, Z=14.78 (P<0.00001) | −2.46 (−3.19, −1.74) I2=0, Z=6.64 (P<0.00001) |
| Follow‐up | ||||||||||
| Intervention effect ≤6 mo | 13 | 1009 | −5.25 (−8.97, −1.53) I2=45%, Z=2.77 (P=0.006) | −18.97 (−21.51, −16.43) I2=82%, Z=14.63 (P<0.00001) | −3.60 (−6.16, −1.05) I2=0, Z=2.77 (P=0.006) | −2.43 (−3.09, −1.78) I2=0, Z=7.28 (P<0.00001) | −5.65 (−9.37, −1.93) I2=72%, Z=2.97 (P=0.003) | −7.1 (−13.69, −0.52) I2=0, Z=2.11 (P=0.03) | −244.40 (−279.97, −208.82) I2=93%, Z=13.46 (P<0.00001) | −2.22 (−2.94, −1.49) I2=0, Z=6.02 (P<0.00001) |
| Intervention effect ≥9 mo | 7 | 9166 | −7.49 (−11.82, −3.17) I2=20%, Z=3.39 (P=0.0007) | −11.57 (−18.65, −4.50) I2=0, Z=3.21 (P=0.001) | −3.30 (−6.78, 0.18)*, Z=1.86 (P=0.06) | −2.20 (−5.04, 0.64)*, Z=1.52 (P=0.13) | −4.55 (−8.92, −0.18) I2=0, Z=2.04 (P=0.04) | −18.30 (−49.32, 12.72)*, Z=1.16 (P=0.25) | −310.37 (−350.24, −270.50) I2=88%, Z=15.26 (P<0.00001) | −2.49 (−3.22, −1.77) I2=0, Z=6.75 (P<0.00001) |
| Dosage of ARNI | ||||||||||
| Medium/high dose ≤50% | 7 | 386 | −18 (−31.89, −4.11)*, Z=2.54 (P=0.01) | −21.68 (−24.46, −18.91), I2=50%, Z=15.31 (P<0.00001) | NR | −2.41 (−3.24, −1.58) I2=0, Z=5.71 (P<0.00001) | NR | NR | −691 (−892.88, −489.12)*, Z=6.71 (P<0.00001) | NR |
| Medium/high dose >50% | 11 | 9671 | −7.93 (−12.15, −3.7) I2=0, Z=3.68 (P=0.0002) | −11.8 (−18.53, −5.06) I2=0, Z=3.43 (P=0.0006) | −3.36 (−5.69, −1.03) I2=0, Z=2.82 (P=0.005) | −2.47 (−3.52, −1.43) I2=0, Z=4.65 (P<0.00001) | −5.81 (−10.51, −1.11) I2=0, Z=2.43 (P=0.02) | −6.75 (−10.6, −2.89), I2=61%, Z=3.43 (P=0.0006) | −308.8 (−349.28, −268.32) I2=85%, Z=14.95 (P<0.00001) | −2.47 (−3.2, −1.75) I2=0, Z=6.67 (P<0.00001) |
| Mean baseline SBP | ||||||||||
| SBP ≤120 mm Hg | 4 | 423 | −18.11 (−35.49, −0.72) I2=0, Z=2.04 (P=0.04) | −20.66 (−40.97, −0.34), I2=0, Z=1.99 (P=0.05) | −3.36 (−5.69, −1.03) I2=0, Z=2.82 (P=0.005) | −2.54 (−3.96, −1.12) I2=0, Z=3.50 (P=0.0005) | −14.44 (−22.61, −6.27)*, Z=3.46 (P=0.0005) | −18.30 (−49.32, 12.72)*, Z=1.16 (P=0.25) | NR | NR |
| SBP >120 mm Hg | 8 | 9324 | −7.93 (−12.17, −3.7) I2=55%, Z=3.67 (P=0.0002) | −20.31 (−22.91, −17.71), I2=79%, Z=15.3 (P<0.00001) | NR | −2.36 (−3.2, −1.52) I2=20%, Z=5.51 (P<0.00001) | −4.55 (−8.92, −0.18) I2=0, Z=2.04 (P=0.04) | −4.6 (−10.91, 1.71)*, Z=1.43 (P=0.15) | −321.46 (−361.22, −281.71) I2=90%, Z=15.85 (P<0.00001) | −2.46 (−3.19, −1.74) I2=0, Z=6.64 (P<0.00001) |
| Different control groups | ||||||||||
| ACEIs | 2 | 8649 | NR | −22 (−24.81, −19.19)*, Z=15.34 (P<0.00001) | NR | −3 (−4.4, −1.6)*, Z=4.21 (P<0.0001) | NR | NR | −479.3 (−574.02, −384.58)*, Z=9.92 (P<0.00001) | −2.5 (−3.24, −1.76)*, Z=6.66 (P<0.00001) |
| ARBs | 3 | 533 | −7.49 (−11.82, −3.17) I2=20%, Z=3.39 (P=0.0007) | −11.57 (−18.65, −4.5), I2=0, Z=3.21 (P=0.001) | −3.30 (−6.78, 0.18)*, Z=1.86 (P=0.06) | −2.20 (−5.04, 0.64)*, Z=1.52 (P=0.13) | −4.55 (−8.92, −0.18) I2=0, Z=2.04 (P=0.04) | −5.14 (−11.33, 1.04), I2=0, Z=1.63 (P=0.1) | −267 (−311.9, −222.1)*, Z=11.66 (P<0.00001) | −0.8 (−5.86, 4.26)*, Z=0.31 (P=0.76) |
| Etiology | ||||||||||
| Ischemic heart disease ≤50% | 6 | 310 | −18.11 (−35.49, −0.72) I2=0, Z=2.04 (P=0.04) | −20.66 (−40.97, −0.34), I2=0, Z=1.99 (P=0.05) | −3.36 (−5.69, −1.03) I2=0, Z=2.82 (P=0.005) | −2.66 (−4.02, −1.29) I2=0, Z=3.82 (P=0.0001) | NR | −18.30 (−49.32, 12.72)*, Z=1.16 (P=0.25) | −977.7 (−2324.81, 369.41)*, Z=1.42 (P=0.15) | NR |
| Ischemic heart disease >50% | 8 | 9194 | −17.47 (−29.12, −5.82) I2=0, Z=2.94 (P=0.003) | −21.58 (−24.34, −18.83), I2=16%,Z=15.34 (P<0.00001) | NR | −2.36 (−3.17, −1.55) I2=0, Z=5.72 (P<0.00001) | NR | −6.72 (−13.94, 0.5)*, Z=1.82 (P=0.07) | −517.5 (−603.25, −431.74) I2=71%, Z=11.83 (P<0.00001) | NR |
| Concomitant therapy | ||||||||||
| MRA ≤50% | 3 | 484 | −7.49 (−11.82, −3.17) I2=20%, Z=3.39 (P=0.0007) | −3.30 (−6.78, 0.18)*, Z=1.86 (P=0.06) | −2.20 (−5.04, 0.64)*, Z=1.52 (P=0.13) | −2.8 (−8.61, 3.01)*, Z=0.94 (P=0.35) | −5.14 (−11.33, 1.04), I2=0, Z=1.63 (P=0.1) | −267 (−311.9, −222.1)*, Z=11.66 (P<0.00001) | −0.8 (−5.86, 4.26)*, Z=0.31 (P=0.76) | |
| MRA >50% | 12 | 9341 | −18.4 (−28.74, −8.05) I2=0, Z=3.48 (P=0.0005) | −21.59 (−24.33, −18.85), I2=0, Z=15.43 (P<0.00001) | −3.60 (−6.16, −1.05) I2=0, Z=2.77 (P=0.006) | −2.43 (−3.09, −1.78) I2=0, Z=7.28 (P<0.00001) | −9.85 (−15.01, −4.7) I2=50%, Z=3.75 (P=0.0002) | −7.1 (−13.69, −0.52) I2=0, Z=2.11 (P=0.03) | −513.66 (−592.64, −434.67) I2=33%, Z=12.75 (P<0.00001) | −2.54 (−3.27, −1.81) I2=0, Z=6.8 (P<0.00001) |
Results at 3‐ to 6‐month follow‐up used unless otherwise stated. Mean differences are pooled estimates from meta‐analysis with 95% CIs. I2 values reported as measure of heterogeneity. Z scores with associated P values reported as test for overall effect. ACEI indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin‐receptor neprilysin inhibitor; EDD, end‐diastolic dimension; EDV, end‐diastolic volume; ESD, end‐systolic dimension; ESV, end‐systolic volume; LAV, left atrial volume; LV, left ventricular; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; MRA, mineralocorticoid receptor antagonist; NR, not reported; NT‐proBNP, N‐terminal pro–brain‐type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; sST2, soluble suppressor of tumorigenesis‐2; 6MWD, 6‐minute walking distance.*Data was available in only one study. (This sentence should start on a new line.)