Of the 506 reduced LVEF patients, 177 (35%) were assigned to the Normal-RAP, 239 (47%) were assigned to the Intermediate-RAP, and 90 (18%) were assigned to the High-RAP groups. Of the 484 non-reduced LVEF patients, 147 (30%) were assigned to the Normal-RAP, 221 (46%) were assigned to the Intermediate-RAP, and 116 (24%) were assigned to the High-RAP groups (Reduced vs. Non-reduced LVEF: p = 0.044).
CLINICAL CHARACTERISTICS. Table 1 shows the patients’ baseline characteristics. Overall, the patients’ mean age was 69 years and two-thirds of the patients were men. The High-RAP group had a significantly lower rate of dyslipidemia, higher rate of atrial fibrillation, and lower systolic blood pressure at discharge compared with the other RAP groups. The laboratory data at discharge showed that the High-RAP group had a lower estimated glomerular filtration rate (eGFR), a higher blood urea nitrogen (BUN) level, and lower hemoglobin and sodium levels, and that the Intermediate-RAP group had a higher BNP level than the other RAP groups. The TTE findings showed that the High-RAP groups had higher LVEF and lower TAPSEs than the other RAP groups, and that as the RAP increased, the PASP increased. Almost 90% of the enrolled patients received furosemide. The High-RAP group was prescribed furosemide more frequently, and beta-blockers and statins less frequently than the other RAP groups. The Normal-RAP group was prescribed mineralocorticoid receptor antagonists less frequently than the other RAP groups.
Table 1
Patients’ baseline characteristics
Variables | All | | Reduced LVEF | | Non-reduced LVEF |
Normal RAP N = 324 | Intermediate RAP N =460 | High RAP N = 90 | p Value | | Normal RAP N =177 | Intermediate RAP N =239 | High RAP N = 90 | p Value | | Normal RAP N =147 | Intermediate RAP N = 221 | High RAP N = 116 | p Value |
Clinical background | | | | | | | | | | | | |
Age, years old | 69.4 ± 15.3 | 69.2 ± 15.4 | 72.2 ± 12.9 | 0.04 | | 65.8 ± 14.7 | 65.1 ± 16.4 | 67.7 ± 15.3 | 0.39 | | 73.7 ± 14.9 | 73.7 ± 12.7 | 75.7 ± 9.4 | 0.33 |
Male | 202 (62%) | 288 (63%) | 147 (71%) | 0.06 | | 130 (73%) | 179 (75%) | 76 (84%) | 0.11 | | 72 (49%) | 109 (49%) | 71 (61%) | 0.08 |
BMI, kg/m2 | 22.5 ± 4.6 | 21.6 ± 4.5 | 21.9 ± 3.1 | 0.10 | | 22.5 ± 4.6 | 21.6 ± 4.5 | 21.9 ± 3.1 | 0.10 | | 22.4 ± 4.7 | 21.8 ± 4.0 | 21.1 ± 4.0 | 0.053 |
Hypertension | 222 (69%) | 293 (64%) | 121 (59%) | 0.07 | | 118 (67%) | 140 (59%) | 56 (62%) | 0.25 | | 104 (71%) | 153 (69%) | 65 (56%) | 0.02 |
Diabetes | 127 (39%) | 176 (38%) | 83 (40%) | 0.88 | | 73 (41%) | 90 (38%) | 35 (39%) | 0.77 | | 54 (37%) | 86 (38%) | 48 (41%) | 0.75 |
Dyslipidemia | 174 (54%) | 234 (51%) | 86 (42%) | 0.02 | | 111 (63%) | 129 (54%) | 45 (50%) | 0.09 | | 63 (43%) | 105 (48%) | 41 (35%) | 0.10 |
Prior revascularization | 74 (23%) | 108 (24%) | 33 (16%) | 0.08 | | 41 (23%) | 65 (27%) | 24 (27%) | 0.63 | | 33 (22%) | 43 (20%) | 9 (8%) | 0.003 |
Atrial fibrillation | 139 (43%) | 214 (49%) | 148 (72%) | < 0.001 | | 69 (40%) | 89 (48%) | 58 (64%) | < 0.001 | | 70 (48%) | 125 (57%) | 90 (78%) | < 0.001 |
Hemodynamics at discharge | | | | | | | | |
Systolic BP, mmHg | 113.9 ± 17.7 | 111.9 ± 17.8 | 108.9 ± 16.1 | 0.006 | | 109.9 ± 17.7 | 107.7 ± 18.5 | 103.9 ± 16.1 | 0.03 | | 118.9 ± 16.5 | 109.4 ± 21.3 | 103.7 ± 14.0 | 0.01 |
Heart rate, bpm | 69.4 ± 11.5 | 79.6 ± 12.9 | 71.1 ± 12. | 0.24 | | 69.5 ± 10.5 | 71.7 ± 13.2 | 70.3 ± 10.7 | 0.18 | | 69.3 ± 12.7 | 70.3 ± 10.7 | 73.0 ± 11.6 | 0.22 |
Lab data at discharge | | | | | | | | | | | | |
Creatinine, mg/dL | 1.35 ± 1.06 | 1.49 ± 1.50 | 1.50 ± 0.91 | 0.29 | | 1.33 ± 0.88 | 1.46 ± 1.37 | 1.63 ± 0.98 | 0.14 | | 1.37 ± 1.24 | 1.51 ± 1.62 | 1.40 ± 0.84 | 0.61 |
eGFR, mL/min/1.73m2 | 48.7 ± 28.0 | 49.1 ± 40.7 | 40.8 ± 25.4 | 0.01 | | 46.3 ± 26.5 | 48.8 ± 47.6 | 35.0 ± 18.2 | 0.01 | | 51.5 ± 29.6 | 49.5 ± 32.2 | 45.4 ± 29.1 | 0.28 |
BUN, mg/dL | 27.3 ± 15.4 | 28.1 ± 15.6 | 36.9 ± 21.4 | < 0.001 | | 26.7 ± 14.7 | 27.5 ± 15.8 | 36.9 ± 23.0 | < 0.001 | | 27.8 ± 16.3 | 28.7 ± 19.2 | 36.8 ± 20.2 | < 0.001 |
Albumin, mg/dL | 3.67 ± 0.52 | 3.65 ± 0.54 | 3.70 ± 0.53 | 0.51 | | 3.76 ± 0.48 | 3.68 ± 0.53 | 3.76 ± 0.50 | 0.24 | | 3.54 ± 0.55 | 3.62 ± 0.55 | 3.66 ± 0.54 | 0.29 |
Hemoglobin, mg/dL | 12.5 ± 2.1 | 12.2 ± 2.1 | 11.5 ± 2.3 | < 0.001 | | 12.9 ± 2.1 | 12.7 ± 2.1 | 12.3 ± 2.5 | 0.14 | | 12.0 ± 2.0 | 11.7 ± 3.2 | 10.8 ± 1.9 | 0.37 |
Sodium, mEq/L | 138.9 ± 8.3 | 138.8 ± 3.3 | 137.3 ± 3.9 | 0.002 | | 138.5 ± 10.7 | 138.3 ± 3.4 | 136.6 ± 3.9 | 0.09 | | 139.4 ± 3.4 | 139.3 ± 3.2 | 137.9 ± 3.8 | < 0.001 |
BNP, pg/mL | 341 ± 351 | 439 ± 537 | 385 ± 501 | 0.048 | | 355 ± 371 | 584 ± 651 | 561 ± 630 | 0.001 | | 323 ± 324 | 306 ± 360 | 235 ± 282 | 0.16 |
CRP, mg/dL | 0.85 ± 1.82 | 0.88 ± 1.81 | 0.91 ± 1.83 | 0.92 | | 0.78 ± 1.36 | 0.78 ± 1.88 | 0.78 ± 1.36 | 0.96 | | 0.93 ± 2.28 | 0.95 ± 1.75 | 1.02 ± 2.13 | 0.26 |
Echocardiographic parameters | | | | | | | | | |
LVEF, % | 38.7 ± 12.0 | 38.5 ± 13.0 | 41.3 ± 13.6 | 0.02 | | 29.4 ± 6.4 | 27.8 ± 7.0 | 27.9 ± 6.8 | 0.04 | | 49.9 ± 6.4 | 49.9 ± 6.5 | 51.8 ± 6.3 | 0.33 |
E/e’ (septal) | 17.4 ± 7.8 | 18.4 ± 9.0 | 18.7 ± 8.2 | 0.24 | | 17.7 ± 8.4 | 19.5 ± 9.1 | 20.3 ± 8.3 | 0.07 | | 17.1 ± 7.1 | 17.0 ± 8.6 | 17.2 ± 8.0 | 0.98 |
TAPSE, mm | 16.9 ± 4.8 | 16.3 ± 5.0 | 15.1 ± 4.9 | 0.004 | | 15.6 ± 4.6 | 14.9 ± 4.4 | 13.2 ± 4.7 | 0.006 | | 18.7 ± 4.5 | 18.0 ± 5.1 | 16.4 ± 4.6 | 0.007 |
PASP, mmHg | 40.0 ± 12.3 | 42.2 ±14.1 | 46.2 ± 15.1 | < 0.001 | | 31.3 ± 11.7 | 39.3 ± 13.8 | 52.6 ± 15.8 | < 0.001 | | 34.2 ± 12.9 | 41.5 ± 14.2 | 50.5 ± 14.2 | < 0.001 |
Maximum IVC, mm | 13.7 ± 3.8 | 16.2 ± 4.5 | 25.7 ± 4.0 | < 0.001 | | 13.6 ± 3.7 | 15.7 ± 4.6 | 25.5 ± 3.4 | < 0.001 | | 13.8 ± 3.8 | 16.7 ± 4.5 | 25.9 ± 4.5 | < 0.001 |
IVC collapsibility, mm | 59.0 ± 8.1 | 33.1 ± 14.8 | 23.1 ± 13.4 | < 0.001 | | 58.6 ± 8.1 | 32.6 ± 15.6 | 21.3 ± 14.5 | < 0.001 | | 59.4 ± 8.2 | 33.6 ± 13.9 | 24.5 ± 12.5 | < 0.001 |
Medications at discharge | | | | | | | | |
Furosemide | 275 (85%) | 398 (87%) | 192 (93%) | 0.01 | | 155 (88%) | 209 (87%) | 80 (89%) | 0.97 | | 120 (82%) | 189 (86%) | 112 (97%) | < 0.001 |
ACEi/ARBs | 272 (84%) | 373 (81%) | 169 (82%) | 0.59 | | 158 (89%) | 207 (87%) | 81 (90%) | 0.63 | | 114 (78%) | 166 (75%) | 88 (76%) | 0.87 |
β-blockers | 257 (79%) | 354 (77%) | 141 (68%) | 0.02 | | 159 (90%) | 210 (88%) | 79 (88%) | 0.81 | | 98 (67%) | 144 (65%) | 62 (53%) | 0.06 |
Mineral corticoid-receptor antagonist | 175 (54%) | 287 (62%) | 128 (62%) | 0.045 | | 108 (61%) | 168 (70%) | 66 (73%) | 0.06 | | 67 (46%) | 119 (54%) | 62 (53%) | 0.26 |
Statin | 167 (52%) | 179 (39%) | 67 (33%) | < 0.001 | | 99 (56%) | 104 (44%) | 34 (38%) | 0.007 | | 68 (46%) | 75 (34%) | 33 (28%) | 0.008 |
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; BMI = body mass index; BNP = B-type natriuretic peptide; BP = blood pressure; BUN = blood urea nitrogen; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; IVC = inferior vena cava; LVEF = left ventricular ejection fraction; PASP = pulmonary artery systolic pressure; RAP = right atrial pressure; TAPSE = tricuspid annular plane systolic excursion. |
The mean age of the patients with reduced LVEF was 65 years, which was 10 years younger than the mean age of the patients with non-reduced LVEF. The rates of hypertension, diabetes, and dyslipidemia were comparable among the different RAP groups in patients with reduced LVEF. The prevalence of atrial fibrillation increased as the RAP rose in the patients with reduced and non-reduced LVEF. At discharge, the systolic blood pressure and serum sodium levels were lower, BUN levels were higher, and the eGFRs were lower in the High-RAP groups of patients with reduced and non-reduced LVEF compared with the other RAP groups. The Normal-RAP group of patients with reduced LVEF had a lower BNP level than the other RAP groups of patients with reduced LVEF. As the RAP increased, the TAPSE declined and the PASP rose in the patients with reduced and non-reduced LVEF. The RAP groups did not differ regarding the use of beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARB), and mineralocorticoid receptor antagonists, and the use of statins was lower in the High-RAP group compared with that in the other RAP groups of patients with reduced and non-reduced LVEF. The use of furosemide was comparable among the RAP groups of patients with reduced LVEF. Furosemide use was more frequent in the High-RAP group than that in the other RAP groups of patients with non-reduced LVEF.
PATIENT PROGNOSES: PRIMARY ENDPOINT. During the observation period after discharge (median follow-up duration was 472 days), the primary endpoint had occurred in 425 patients (43%) overall. The Kaplan-Meier curves showed that the rates of the composite endpoint of cardiovascular death and HHF were higher in the patients with higher RAP (log-rank test for trend: p < 0.001) (Figure 2A). Of the patients with reduced and non-reduced LVEF, 247 (49%) and 178 (37%), respectively, experienced the primary endpoint. The Kaplan-Meier analysis showed the RAP groups of patients with reduced LVEF did not differ regarding the incidence of the primary endpoint (log-rank for trend: p = 0.10) (Figure 2B). Among the patients with non-reduced LVEF, the High-RAP group showed a higher event rate compared with that in the other RAP groups (p < 0.001) (Figure 2C). The univariate Cox regression analysis of the patients with non-reduced LVEF showed that age, the body mass index, hypertension, atrial fibrillation, eGFR, BUN, hemoglobin, and sodium levels at discharge, the furosemide dose, the use of ACEi/ARB, beta-blockers, and statins, and the RAP classification were related to the incidence of the primary endpoint (Table 2). The multivariate Cox regression analysis that accounted for the covariates, showed that the RAP classification persisted as an independent predictor of the primary endpoint (adjusted hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.01–1.59). The interaction between the RAP groups and the LVEF regarding the primary endpoint was significant (pinteraction = 0.007).
Table 2
Cox regression analysis of the primary endpoint in patients with non-reduced LVEF
Covariants | Univariate analysis | | Multivariate analysis |
HR (95%CI) | p Value | HR (95%CI) | p Value |
Age | 1.03 (1.01-1.05) | 0.002 | | 1.01 (0.99-1.02) | 0.43 |
BMI | 0.93 (0.89-0.98) | 0.007 | | 0.99 (0.94-1.03) | 0.51 |
Hypertension | 0.63 (0.43-0.93) | 0.02 | | 0.96 (0.67-1.37) | 0.82 |
Atrial fibrillation | 1.92 (1.25-2.95) | 0.003 | | 1.59 (1.11-2.27) | 0.01 |
BUN | 1.02 (1.01-1.03) | < 0.001 | | 1.01 (1.00-1.02) | 0.04 |
Hemoglobin | 0.85 (0.77-0.94) | 0.002 | | 0.94 (0.86-1.02) | 0.14 |
Sodium | 0.92 (0.87-0.96) | < 0.001 | | 0.96 (0.91-1.01) | 0.10 |
Furosemide | 3.82 (1.67-8.74) | 0.002 | | 2.03 (0.99-4.13) | 0.052 |
ACEi/ARBs | 0.62 (0.42-0.92) | 0.02 | | 0.52 (0.37-0.74) | < 0.001 |
β-blockers | 0.67 (0.46-0.98) | 0.04 | | 0.61 (0.44-0.856) | 0.003 |
RAP classification | 1.55 (1.12-2.01) | 0.001 | | 1.26 (1.01-1.59) | 0.04 |
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; BMI = body mass index; BUN = blood urea nitrogen; RAP = right atrial pressure. |
PATIENT PROGNOSES: CARDIOVASCULAR DEATH AND REHOSPITALIZATION FOR HEART FAILURE. Regarding cardiovascular death, HF caused 51 deaths (74%), and 16 (23%) sudden cardiac deaths and 3 (4%) strokes occurred in the patients with reduced LVEF. Among the patients with non-reduced LVEF, HF caused 41 deaths (80%), and 7 (14%) sudden cardiac deaths, 2 (4%) strokes, and 1 (2%) cardiovascular hemorrhage occurred (Supplemental Table 1).
Overall, the patients with higher RAP had higher cardiovascular mortality rates (log-rank test for trend: p < 0.001) (Figure 3A). Among the patients with reduced LVEF, the cardiovascular mortality rate was lower in the Normal-RAP group compared with the rates in the Intermediate-RAP and High-RAP groups (p < 0.001) (Figure 3B). Among the patients with non-reduced LVEF, the cardiovascular mortality rate was higher in the High-RAP group compared with the rates in the Intermediate-RAP and Normal-RAP groups (p < 0.001) (Figure 3C).
The univariate Cox regression analysis of the patients with reduced LVEF showed that age, the body mass index, atrial fibrillation, BUN, hemoglobin, and BNP levels at discharge, the TAPSE, and the RAP classification were related to the incidence of cardiovascular death (Table 3). The multivariate Cox regression analysis that accounted for the covariates, showed that the RAP classification persisted as an independent predictor of cardiovascular death (adjusted HR: 1.78; 95% CI: 1.05–2.99). The univariate Cox regression analysis of the patients with non-reduced LVEF, showed that the body mass index, hypertension, BUN and serum sodium levels at discharge, and the RAP classification were related to the incidence of cardiovascular death (Table 3). The multivariate Cox regression analysis that accounted for the covariates, showed that the RAP classification persisted as an independent predictor of cardiovascular death (adjusted HR: 2.33; 95% CI: 1.45–3.74).
Table 3
Cox regression analysis of the cardiovascular death in patients with reduced LVEF
Covariants | Univariate analysis | | Multivariate analysis |
HR (95%CI) | p Value | HR (95%CI) | p Value |
Reduced LVEF | | | | | |
Age | 1.03 (1.02-1.05) | < 0.001 | | 1.02 (0.99-1.06) | 0.12 |
BMI | 0.87 (0.81-0.93) | < 0.001 | | 0.96 (0.86-1.07) | 0.44 |
Atrial fibrillation | 2.12 (1.32-3.42) | 0.002 | | 1.68 (0.78-3.59) | 0.18 |
BUN | 1.02 (1.01-1.03) | < 0.001 | | 1.01 (0.98-1.04) | 0.48 |
Hemoglobin | 0.78 (0.69-0.87) | < 0.001 | | 0.84 (0.68-1.03) | 0.10 |
Log. BNP | 9.61 (4.80-19.2) | < 0.001 | | 3.21 (1.10-9.36) | 0.03 |
TAPSE | 0.91 (0.46-0.98) | 0.005 | | 0.93 (0.86-14.00) | 0.06 |
RAP classification | 1.85 (1.35-2.55) | < 0.001 | | 1.78 (1.05-2.99) | 0.03 |
Non-reduced LVEF | | | | | |
BMI | 0.80 (0.73-0.88) | < 0.001 | | 0.85 (0.77-0.93) | < 0.001 |
Hypertension | 0.36 (0.21-0.64) | < 0.001 | | 0.67 (0.37-1.23) | 0.20 |
BUN | 1.02 (1.01-1.03) | 0.009 | | 1.01 (0.99-1.03) | 0.24 |
Sodium | 0.90 (0.84-0.97) | 0.003 | | 0.97 (0.89-1.06) | 0.53 |
RAP classification | 2.93 (1.91-4.47) | < 0.001 | | 2.33 (1.45-3.74) | < 0.001 |
BMI = body mass index; BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; RAP = right atrial pressure. |
The Kaplan-Meier curves showed that the patients with higher RAP had a higher incidence of HHF (log-rank test for trend: p = 0.002) (Figure 2D). The HHF rate did not differ among the RAP groups of patients with reduced LVEF (p = 0.33) (Figure 2E). Among the patients with non-reduced LVEF, the HHF rate was higher in the High-RAP group compared with the rates in the other RAP groups (p < 0.001) (Figure 2F). The HHF rate was even worse in the High-RAP group of patients with non-reduced LVEF than that in the High-RAP group of patients with reduced LVEF (2-year event-free survival rate: 46.3% vs. 56.6%).The univariate Cox regression analysis of the patients with non-reduced LVEF showed that the body mass index, hypertension, atrial fibrillation, eGFR, BUN, hemoglobin, and serum sodium levels at discharge, and the RAP classification were related to the HHF rate (Table 4). The multivariate Cox regression analysis that accounted for the covariates, showed that the RAP classification persisted as an independent predictor of HHF (adjusted HR: 1.39; 95% CI: 1.09–1.78).
Table 4
Cox regression analysis of the heart failure rehospitalization in patients with non-reduced LVEF
Covariants | Univariate analysis | | Multivariate analysis |
HR (95%CI) | p Value | HR (95%CI) | p Value |
BMI | 0.99 (0.91-0.99) | 0.02 | | 0.98 (0.93-1.02) | 0.30 |
Hypertension | 0.69 (0.50-0.94) | 0.02 | | 0.84 (0.59-1.19) | 0.32 |
Atrial fibrillation | 1.66 (1.18-2.32) | 0.003 | | 1.55 (1.07-2.25) | 0.02 |
eGFR | 0.99 (0.99-0.999) | 0.02 | | 0.99 (0.99-1.00) | 0.10 |
BUN | 1.02 (1.01-1.03) | < 0.001 | | 1.01 (0.99-1.02) | 0.45 |
Hemoglobin | 0.82 (0.76-0.90) | < 0.001 | | 0.91 (0.83-1.00) | 0.04 |
Sodium | 0.93 (0.89-0.97) | < 0.001 | | 0.96 (0.92-1.02) | 0.16 |
RAP classification | 1.60 (1.28-1.28) | < 0.001 | | 1.39 (1.09-1.78) | 0.007 |
BMI = body mass index; BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; RAP = right atrial pressure. |