Vericiguat - Entresto

Descrittiva

Table 1

Characteristic Overall
N = 571		 Entresto STOP
N = 301		 Vericiguat STOP
N = 271		 p-value2
Età (anni) 70.47 ± 10.93 69.73 ± 12.00 71.30 ± 9.77 0.575
Genere


>0.999
    M 47 (82%) 25 (83%) 22 (81%)
    F 10 (18%) 5 (17%) 5 (19%)
Peso (kg) 79.75 ± 8.91 75.70 ± 8.42 84.26 ± 7.22 <0.001
Altezza (cm) 175.86 ± 8.44 175.83 ± 8.54 175.89 ± 8.50 0.695
BMI (kg/m²) 26.01 ± 4.15 24.74 ± 4.23 27.41 ± 3.65 0.009
BSA (m²) 1.97 ± 0.12 1.92 ± 0.10 2.03 ± 0.11 0.001
ICD 53 (93%) 28 (93%) 25 (93%) >0.999
CRT 20 (35%) 8 (27%) 12 (44%) 0.160
Diabete mellito tipo 2 24 (42%) 15 (50%) 9 (33%) 0.203
Ipertensione 41 (72%) 22 (73%) 19 (70%) 0.804
Fibrillazione atriale 23 (40%) 13 (43%) 10 (37%) 0.629
Tempo all'interruzione (giorni) 147.37 ± 18.22 146.00 ± 20.99 148.89 ± 14.79 0.405
1 Mean ± SD; n (%)
2 Wilcoxon rank sum test; Fisher’s exact test; Pearson’s Chi-squared test

Table 2 and 3 (strata per Timepoint and Stop Group)

Characteristic
Baseline
3 Months
6 Months
12 Months
Entresto STOP
N = 301		 Vericiguat STOP
N = 271		 p-value2 Entresto STOP
N = 301		 Vericiguat STOP
N = 271		 p-value3 Entresto STOP
N = 301		 Vericiguat STOP
N = 271		 p-value4 Entresto STOP
N = 301		 Vericiguat STOP
N = 271		 p-value4
Systolic BP (mmHg) 97.70 ± 7.57 98.22 ± 9.22 0.987 93.20 ± 6.46 90.19 ± 7.78 0.110 88.50 ± 5.44 82.96 ± 5.42 0.001 102.47 ± 4.29 89.26 ± 4.54 <0.001
Diastolic BP (mmHg) 73.53 ± 6.03 73.07 ± 5.09 0.754 68.67 ± 6.29 67.96 ± 5.24 0.619 61.17 ± 9.35 63.52 ± 6.77 0.267 71.40 ± 5.24 65.74 ± 7.68 0.002
TAPSE (mm) 19.03 ± 1.50 19.48 ± 2.56 0.353 19.07 ± 1.44 20.41 ± 2.08 0.009 20.10 ± 1.16 20.15 ± 1.92 0.909 19.83 ± 1.05 18.22 ± 1.25 <0.001
Pulmonary artery systolic pressure (mmHg) 51.20 ± 8.77 48.89 ± 8.89 0.279 46.47 ± 7.70 40.96 ± 6.57 0.009 43.57 ± 7.09 37.89 ± 9.00 0.012 39.87 ± 7.59 45.07 ± 9.72 0.042
LVEF (%) 0.29 ± 0.05 0.29 ± 0.04 0.897 0.31 ± 0.04 0.32 ± 0.04 0.217 0.33 ± 0.03 0.34 ± 0.04 0.322 0.35 ± 0.03 0.30 ± 0.06 0.004
Creatinine (mg/dL) 1.56 ± 0.35 1.59 ± 0.26 0.910 1.60 ± 0.29 1.59 ± 0.28 0.675 1.65 ± 0.28 1.60 ± 0.26 0.489 1.43 ± 0.34 1.69 ± 0.23 0.006
NT-proBNP (pg/mL) 2,272.03 ± 1,607.30 1,912.11 ± 1,061.21 0.823 1,453.70 ± 1,039.45 1,411.70 ± 843.45 0.898 1,425.67 ± 1,083.14 1,344.52 ± 795.85 0.911 2,360.67 ± 3,134.48 1,984.07 ± 1,668.15 0.886
Diastolic dysfunction 2.60 ± 0.50 2.37 ± 0.63 0.175 2.23 ± 0.50 2.04 ± 0.59 0.200 1.83 ± 0.59 1.74 ± 0.59 0.559 1.67 ± 0.71 2.07 ± 0.68 0.030
Vericiguat dose




0.944

<0.001

<0.001
    None 0 (0%) 0 (0%)
0 (0%) 0 (0%)
1 (3.3%) 27 (100%)
0 (0%) 27 (100%)
    2.5 mg 30 (100%) 27 (100%)
18 (60%) 15 (56%)
12 (40%) 0 (0%)
23 (77%) 0 (0%)
    5 mg 0 (0%) 0 (0%)
12 (40%) 12 (44%)
17 (57%) 0 (0%)
7 (23%) 0 (0%)
Sacubitril/valsartan dose

>0.999




<0.001

<0.001
    None 0 (0%) 0 (0%)
0 (0%) 0 (0%)
30 (100%) 0 (0%)
30 (100%) 0 (0%)
    24/26 mg 12 (40%) 10 (37%)
30 (100%) 27 (100%)
0 (0%) 27 (100%)
0 (0%) 27 (100%)
    49/51 mg 18 (60%) 17 (63%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
1 Mean ± SD; n (%)
2 Wilcoxon rank sum test; NA; Pearson’s Chi-squared test
3 Wilcoxon rank sum test; Pearson’s Chi-squared test; NA
4 Wilcoxon rank sum test; Pearson’s Chi-squared test
Characteristic
Entresto STOP
Vericiguat STOP
Baseline
N = 301		 3 Months
N = 301		 6 Months
N = 301		 12 Months
N = 301		 p-value2 Baseline
N = 271		 3 Months
N = 271		 6 Months
N = 271		 12 Months
N = 271		 p-value3
ID 15.50 ± 8.80 15.50 ± 8.80 15.50 ± 8.80 15.50 ± 8.80 >0.999 44.00 ± 7.94 44.00 ± 7.94 44.00 ± 7.94 44.00 ± 7.94 >0.999
Systolic BP (mmHg) 97.70 ± 7.57 93.20 ± 6.46 88.50 ± 5.44 102.47 ± 4.29 <0.001 98.22 ± 9.22 90.19 ± 7.78 82.96 ± 5.42 89.26 ± 4.54 <0.001
Diastolic BP (mmHg) 73.53 ± 6.03 68.67 ± 6.29 61.17 ± 9.35 71.40 ± 5.24 <0.001 73.07 ± 5.09 67.96 ± 5.24 63.52 ± 6.77 65.74 ± 7.68 <0.001
TAPSE (mm) 19.03 ± 1.50 19.07 ± 1.44 20.10 ± 1.16 19.83 ± 1.05 0.001 19.48 ± 2.56 20.41 ± 2.08 20.15 ± 1.92 18.22 ± 1.25 <0.001
Pulmonary artery systolic pressure (mmHg) 51.20 ± 8.77 46.47 ± 7.70 43.57 ± 7.09 39.87 ± 7.59 <0.001 48.89 ± 8.89 40.96 ± 6.57 37.89 ± 9.00 45.07 ± 9.72 <0.001
LVEF (%) 0.29 ± 0.05 0.31 ± 0.04 0.33 ± 0.03 0.35 ± 0.03 <0.001 0.29 ± 0.04 0.32 ± 0.04 0.34 ± 0.04 0.30 ± 0.06 <0.001
Creatinine (mg/dL) 1.56 ± 0.35 1.60 ± 0.29 1.65 ± 0.28 1.43 ± 0.34 0.174 1.59 ± 0.26 1.59 ± 0.28 1.60 ± 0.26 1.69 ± 0.23 0.283
NT-proBNP (pg/mL) 1,890.00 (1,254.00 - 2,900.00) 1,252.00 (900.00 - 1,650.00) 1,290.00 (750.00 - 1,700.00) 1,415.00 (849.00 - 2,450.00) 0.058 1,690.00 (700.00 - 2,868.00) 1,300.00 (686.00 - 1,800.00) 1,264.00 (600.00 - 1,789.00) 1,400.00 (820.00 - 2,600.00) 0.146
Vericiguat dose



<0.001



<0.001
    None 0 (0%) 0 (0%) 1 (3.3%) 0 (0%)
0 (0%) 0 (0%) 27 (100%) 27 (100%)
    2.5 mg 30 (100%) 18 (60%) 12 (40%) 23 (77%)
27 (100%) 15 (56%) 0 (0%) 0 (0%)
    5 mg 0 (0%) 12 (40%) 17 (57%) 7 (23%)
0 (0%) 12 (44%) 0 (0%) 0 (0%)
Sacubitril/valsartan dose



<0.001



<0.001
    None 0 (0%) 0 (0%) 30 (100%) 30 (100%)
0 (0%) 0 (0%) 0 (0%) 0 (0%)
    24/26 mg 12 (40%) 30 (100%) 0 (0%) 0 (0%)
10 (37%) 27 (100%) 27 (100%) 27 (100%)
    49/51 mg 18 (60%) 0 (0%) 0 (0%) 0 (0%)
17 (63%) 0 (0%) 0 (0%) 0 (0%)
Diastolic dysfunction (grade)



<0.001



0.033
    Grade 1 0 (0%) 1 (3.3%) 8 (27%) 14 (47%)
2 (7.4%) 4 (15%) 9 (33%) 5 (19%)
    Grade 2 12 (40%) 21 (70%) 19 (63%) 12 (40%)
13 (48%) 18 (67%) 16 (59%) 15 (56%)
    Grade 3 18 (60%) 8 (27%) 3 (10%) 4 (13%)
12 (44%) 5 (19%) 2 (7.4%) 7 (26%)
1 Mean ± SD; Median (Q1 - Q3); n (%)
2 Kruskal-Wallis rank sum test; Fisher’s exact test; Pearson’s Chi-squared test
3 Kruskal-Wallis rank sum test; Fisher’s exact test

Figures

Modello misto lineare

Characteristic Beta 95% CI p-value
Gruppo


    Entresto STOP — —
    Vericiguat STOP 0.00 -0.02, 0.03 0.7
Tempo


    Baseline — —
    3 Months 0.02 0.01, 0.04 0.002
    6 Months 0.04 0.03, 0.06 <0.001
    12 Months 0.06 0.05, 0.08 <0.001
Interazione Gruppo × Tempo


    Vericiguat STOP * 3 Months 0.01 -0.01, 0.03 0.4
    Vericiguat STOP * 6 Months 0.01 -0.01, 0.03 0.5
    Vericiguat STOP * 12 Months -0.05 -0.07, -0.03 <0.001
Abbreviation: CI = Confidence Interval

Characteristic Beta 95% CI p-value
Gruppo


    Entresto STOP — —
    Vericiguat STOP 0.52 -2.9, 3.9 0.8
Tempo


    Baseline — —
    3 Months -4.5 -6.8, -2.2 <0.001
    6 Months -9.2 -11, -6.9 <0.001
    12 Months 4.8 2.5, 7.1 <0.001
Interazione Gruppo × Tempo


    Vericiguat STOP * 3 Months -3.5 -6.9, -0.21 0.037
    Vericiguat STOP * 6 Months -6.1 -9.4, -2.7 <0.001
    Vericiguat STOP * 12 Months -14 -17, -10 <0.001
Abbreviation: CI = Confidence Interval

Characteristic Beta 95% CI p-value
Gruppo


    Entresto STOP — —
    Vericiguat STOP -360 -1,196, 476 0.4
Tempo


    Baseline — —
    3 Months -818 -1,528, -109 0.024
    6 Months -846 -1,556, -137 0.020
    12 Months 89 -621, 798 0.8
Interazione Gruppo × Tempo


    Vericiguat STOP * 3 Months 318 -713, 1,349 0.5
    Vericiguat STOP * 6 Months 279 -752, 1,310 0.6
    Vericiguat STOP * 12 Months -17 -1,048, 1,014 >0.9
Abbreviation: CI = Confidence Interval

Characteristic Beta 95% CI p-value
Gruppo


    Entresto STOP — —
    Vericiguat STOP -2.3 -6.6, 2.0 0.3
Tempo


    Baseline — —
    3 Months -4.7 -7.3, -2.1 <0.001
    6 Months -7.6 -10, -5.0 <0.001
    12 Months -11 -14, -8.7 <0.001
Interazione Gruppo × Tempo


    Vericiguat STOP * 3 Months -3.2 -7.0, 0.58 0.10
    Vericiguat STOP * 6 Months -3.4 -7.1, 0.41 0.080
    Vericiguat STOP * 12 Months 7.5 3.7, 11 <0.001
Abbreviation: CI = Confidence Interval

Characteristic Beta 95% CI p-value
Gruppo


    Entresto STOP — —
    Vericiguat STOP 0.45 -0.43, 1.3 0.3
Tempo


    Baseline — —
    3 Months 0.03 -0.62, 0.69 >0.9
    6 Months 1.1 0.41, 1.7 0.002
    12 Months 0.80 0.14, 1.5 0.018
Interazione Gruppo × Tempo


    Vericiguat STOP * 3 Months 0.89 -0.06, 1.8 0.067
    Vericiguat STOP * 6 Months -0.40 -1.4, 0.56 0.4
    Vericiguat STOP * 12 Months -2.1 -3.0, -1.1 <0.001
Abbreviation: CI = Confidence Interval

Characteristic Beta 95% CI p-value
Gruppo


    Entresto STOP — —
    Vericiguat STOP 0.03 -0.13, 0.18 0.7
Tempo


    Baseline — —
    3 Months 0.04 -0.05, 0.14 0.4
    6 Months 0.09 -0.01, 0.19 0.064
    12 Months -0.13 -0.22, -0.03 0.010
Interazione Gruppo × Tempo


    Vericiguat STOP * 3 Months -0.04 -0.18, 0.10 0.5
    Vericiguat STOP * 6 Months -0.07 -0.21, 0.07 0.3
    Vericiguat STOP * 12 Months 0.23 0.10, 0.37 0.001
Abbreviation: CI = Confidence Interval

Modello a effetti misti per dati ordinali

Characteristic OR 95% CI p-value
Gruppo: Vericiguat STOP vs Entresto STOP

0.033
    Entresto STOP — —
    Vericiguat STOP 0.21 0.05, 0.88
Tempo

<0.001
    Baseline — —
    3 Months 0.24 0.08, 0.74
    6 Months 0.02 0.01, 0.08
    12 Months 0.00 0.00, 0.01
Interazione Gruppo × Tempo

<0.001
    Vericiguat STOP * 3 Months 0.41 0.08, 2.02
    Vericiguat STOP * 6 Months 1.61 0.32, 8.06
    Vericiguat STOP * 12 Months 178 26.9, 1,174
Abbreviations: CI = Confidence Interval, OR = Odds Ratio
Characteristic OR 95% CI p-value
Gruppo: Vericiguat STOP vs Entresto STOP

0.13
    Entresto STOP — —
    Vericiguat STOP 0.30 0.06, 1.41
Tempo

<0.001
    Baseline — —
    3 Months 0.15 0.04, 0.52
    6 Months 0.02 0.01, 0.10
    12 Months 0.01 0.00, 0.04
Interazione Gruppo × Tempo

0.003
    Vericiguat STOP * 3 Months 1.33 0.25, 7.21
    Vericiguat STOP * 6 Months 2.13 0.39, 11.6
    Vericiguat STOP * 12 Months 21.5 3.52, 132
Abbreviations: CI = Confidence Interval, OR = Odds Ratio

Survival Analysis

Call:
coxph(formula = surv_obj ~ stop, data = df)

  n= 57, number of events= 57 

                       coef exp(coef) se(coef)     z Pr(>|z|)
stopVericiguat STOP 0.06046   1.06232  0.27959 0.216    0.829

                    exp(coef) exp(-coef) lower .95 upper .95
stopVericiguat STOP     1.062     0.9413    0.6141     1.838

Concordance= 0.466  (se = 0.04 )
Likelihood ratio test= 0.05  on 1 df,   p=0.8
Wald test            = 0.05  on 1 df,   p=0.8
Score (logrank) test = 0.05  on 1 df,   p=0.8

Regressioni

Characteristic OR 95% CI p-value
age 0.95 0.88, 1.02 0.2
gender


    M — —
    F 11.4 1.50, 129 0.028
bmi 1.14 0.94, 1.43 0.2
bsa 11,960,242 964, 6,226,903,252,668 0.004
fe_percent_0 0.00 0.00, 2,671 0.2
nt_pro_bnp_0 1.00 1.00, 1.00 0.8
nyha_0 0.45 0.14, 1.28 0.2
crea_0 2.09 0.15, 34.6 0.6
Abbreviations: CI = Confidence Interval, OR = Odds Ratio 
Competing Risks Regression

Call:
crr(ftime = df$treat_dis_days, fstatus = df$event_type, cov1 = model.matrix(~age + 
    gender + fe_percent_0 + nyha_0 + log_ntp0, data = df)[, -1])

                coef exp(coef) se(coef)      z p-value
age          -0.0158    0.9843   0.0197 -0.803   0.420
genderF      -0.2470    0.7812   0.5552 -0.445   0.660
fe_percent_0 -3.2258    0.0397   5.7154 -0.564   0.570
nyha_0        0.6219    1.8624   0.2921  2.129   0.033
log_ntp0      0.0567    1.0583   0.2896  0.196   0.840

             exp(coef) exp(-coef)     2.5%   97.5%
age             0.9843      1.016 9.47e-01    1.02
genderF         0.7812      1.280 2.63e-01    2.32
fe_percent_0    0.0397     25.173 5.42e-07 2910.75
nyha_0          1.8624      0.537 1.05e+00    3.30
log_ntp0        1.0583      0.945 6.00e-01    1.87

Num. cases = 57
Pseudo Log-likelihood = -108 
Pseudo likelihood ratio test = 7.01  on 5 df,

Variabile

sHR

CI 2.5%

CI 97.5%

p-value

age

0.984

0.947

1.023

0.420

genderF

0.781

0.263

2.319

0.660

fe_percent_0

0.040

0.000

2,911.352

0.570

nyha_0

1.862

1.051

3.301

0.033

log_ntp0

1.058

0.600

1.867

0.840