Effects of Carperitide on Degree of Pulmonary Congestion in Treatment of Acute Heart Failure
Article ID: CJ-18-0057
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Article ID: CJ-18-0057
Background: Carperitide is used to treat acute heart failure (AHF) in Japan. Whether the degree of pulmonary congestion is associated with the effects of carperitide on AHF is unclear.
Methods and Results: We retrospectively investigated the in-hospital outcomes and prognoses of 742 patients hospitalized for AHF between February 2015 and January 2017 and classified them into carperitide and non-carperitide groups, stratified according to the degree of pulmonary congestion. The median follow-up duration after admission was 231 days. In patients with moderate–severe pulmonary congestion, the rate of remaining congestion on chest X-ray at discharge was lower in the carperitide group than in the non-carperitide group (1.5% vs. 9.0%, P=0.004). Also, the carperitide group had significant reduction in a composite of all-cause death or rehospitalization for HF (adjusted hazard ratio, 0.62; 95% CI: 0.41–0.93; P=0.02). In patients with no–mild pulmonary congestion, carperitide was not associated with better clinical outcome.
Conclusions: In the treatment of AHF with moderate–severe pulmonary congestion, carperitide is associated with more effective decongestion in the short term and better prognosis in the long term.
Acute heart failure (AHF) is the most common cause of hospitalization in many countries. It is associated with high in-hospital and post-discharge mortality rates and rehospitalization rates. A few promising drugs for AHF have been developed and are currently under investigation, but they have yet to fully improve clinical outcome.
Since the launch of carperitide in 1995, a low-dose regimen has been widely used for treating AHF in Japan, following previous Japanese studies showing that its cardiorenal protective effect improves prognosis.1–4 Recently, carperitide was found to increase the in-hospital mortality rate in AHF patients, and the effects of carperitide on the prognosis of AHF are currently controversial.5,6 We hypothesized that carperitide is effective in treating AHF with pulmonary congestion by promoting diuresis and vasodilation. The aim of this study was to investigate the effects of carperitide in AHF according to the degree of pulmonary congestion.
A total of 911 consecutive patients who were admitted to Kurashiki Central Hospital, Japan for AHF between February 2015 and January 2017 were evaluated, excluding 12 with insufficient data, 57 with acute coronary syndrome, 77 with admission systolic blood pressure (SBP) <100 mmHg, and 23 with end-stage renal disease requiring hemodialysis. Consequently, 742 patients were included in the final analysis (Figure 1A). Patients who started to receive carperitide ≤24 h after admission were assigned to the carperitide group. The carperitide group consisted of 219 patients, 216 (98.6%) of whom started to receive carperitide at the time of admission. In the non-carperitide group, which consisted of 523 patients, only 25 patients (4.8%) received carperitide >24 h after admission, and the remainder did not receive carperitide at all.
Subject selection for (A) primary and (B) propensity score-matched analysis. ACS, acute coronary syndrome; ESRD, end-stage renal disease; SBP, systolic blood pressure.
We compared the short- and long-term outcomes between the carperitide and non-carperitide groups, stratified according to the degree of pulmonary congestion. Of the 742 patients, 358 had moderate–severe pulmonary congestion (carperitide group, n=140; 39.1%; non-carperitide group, n=218; 60.9%) and 384 had no–mild pulmonary congestion (carperitide group, n=79; 20.6%; non-carperitide group, n=305; 79.4%; Figure 1A).
The effects of carperitide were assessed based on an as-treated analysis. Follow-up was commenced on the day of admission.
The study protocol was approved by the Institutional Review Board. The study was conducted in accordance with the provisions of the Declaration of Helsinki and the guidelines for epidemiological studies issued by the Ministry of Health, Labour, and Welfare of Japan. Patient participation was obtained using an opt-out methodology.
Data Collection and DefinitionsAHF was defined using the modified Framingham criteria. Baseline clinical information was collected by reviewing the hospital charts or database. Pulmonary congestion was assessed on conventional chest X-ray on admission (Table S1).7 Follow-up information was collected mainly by reviewing the hospital charts, and additional information was collected through contact with patients, their family members, and/or referring physicians by sending letters asking survival status, symptoms, and subsequent hospitalization. The short-term outcome measures were in-hospital outcomes including 24-h urinary output; days to decongestion on chest X-ray; in-hospital death; change in creatinine from admission to discharge; and symptoms (i.e., congestion on chest X-ray, and pleural effusion on chest X-ray) remaining at discharge. The long-term outcome measures were all-cause death, rehospitalization for HF, and a composite of all-cause death or rehospitalization for HF. Rehospitalization for HF was defined as rehospitalization for worsening HF.
Institute Carperitide ProtocolAt Kurashiki Central Hospital, carperitide is given continuously by i.v. infusion to patients with SBP ≥110 mmHg according to attending physician judgement. The starting dose is 0.01–0.05 μg/kg/min, which can be increased in accordance with the patient’s physical condition, and the maximum dose is 0.05 μg/kg/min. When SBP falls below 100 mmHg or a decrease in urine output caused by decreased blood pressure occurs, carperitide must be reduced or discontinued. The treatment period is determined by the attending physician.
Statistical AnalysisCategorical variables are presented as numbers and percentages and were compared using chi-squared test or Fisher’s exact test. Continuous variables are presented as mean±SD or median (IQR). Continuous variables were compared using Student’s t-test or Wilcoxon rank sum test based on distribution. The Kaplan-Meier method was used to calculate the cumulative incidence of events, and the differences were assessed using log-rank test.
Cox proportional hazard models were used to estimate the adjusted risk of the carperitide group relative to the non-carperitide group for all-cause death, rehospitalization for HF, and a composite of all-cause death or rehospitalization for HF. We selected 10 clinically relevant factors listed in Table 1 as risk-adjusting variables and constructed parsimonious models with a limited number of variables for all-cause death and rehospitalization for HF because the number of patients with these events was too small to construct non-parsimonious models. We selected 5 clinically relevant variables listed in Table 1 as risk-adjusted variables for parsimonious models. Continuous variables were dichotomized according to the median or to clinically meaningful reference values. The long-term clinical risks are expressed as hazard ratios and 95% CI. In addition, we conducted a propensity score-matched analysis as a sensitivity analysis and compared the carperitide group with the non-carperitide group stratified according to degree of pulmonary congestion (Figure 1B; Table S2; Figure S1). Differences were considered statistically significant at P<0.05. All analyses were performed using JMP version 9 (SAS Institute, Cary, NC, USA).
| Variables | Moderate–severe pulmonary congestion | No–mild pulmonary congestion | ||||
|---|---|---|---|---|---|---|
| Carperitide (n=140) |
Non-carperitide (n=218) |
P-value | Carperitide (n=79) |
Non-carperitide (n=305) |
P-value | |
| Age (years) | 77.7±12.4 | 79.8±11.2 | 0.12 | 77.1±15.0 | 78.4±12.2 | 0.82 |
| Age ≥80 years†,‡ | 75 (54) | 129 (59) | 0.30 | 44 (56) | 178 (58) | 0.67 |
| Men | 76 (54) | 108 (50) | 0.38 | 51 (65) | 170 (56) | 0.16 |
| Body weight (kg) | 55.8±16.0 | 53.1±13.5 | 0.17 | 59.0±22.1 | 54.4±13.8 | 0.31 |
| Body mass index (kg/m2) | 22.8±4.6 | 22.0±4.1 | 0.20 | 23.9±6.3 | 22.4±4.2 | 0.29 |
| Body mass index <22 | 62 (48) | 102 (54) | 0.29 | 33 (47) | 138 (51) | 0.54 |
| First hospitalization for heart failure†,‡ | 101 (72) | 157 (72) | 0.98 | 65 (82) | 217 (71) | 0.046 |
| Current smoking | 15 (11) | 18 (8) | 0.42 | 10 (13) | 30 (10) | 0.45 |
| Past smoking | 67 (48) | 98 (45) | 0.55 | 44 (56) | 143 (47) | 0.14 |
| Baseline cardiovascular diseases | ||||||
| Ischemic heart disease | 55 (39) | 71 (33) | 0.19 | 28 (35) | 69 (23) | 0.02 |
| Cardiomyopathy | 14 (10) | 15 (7) | 0.29 | 9 (11) | 30 (10) | 0.68 |
| Hypertensive heart disease | 43 (31) | 31 (14) | <0.001 | 18 (23) | 42 (14) | 0.049 |
| Valvular heart disease | 11 (8) | 63 (29) | <0.001 | 14 (18) | 78 (26) | 0.15 |
| Others | 17 (12) | 38 (17) | 0.18 | 10 (13) | 86 (28) | 0.005 |
| Concomitant diseases | ||||||
| Hypertension | 120 (86) | 182 (83) | 0.57 | 64 (81) | 217 (71) | 0.08 |
| Dyslipidemia | 55 (39) | 75 (34) | 0.35 | 31 (39) | 102 (33) | 0.33 |
| Diabetes mellitus | 50 (36) | 84 (39) | 0.59 | 32 (41) | 87 (29) | 0.04 |
| Prior MI | 48 (34) | 60 (28) | 0.18 | 24 (30) | 74 (24) | 0.27 |
| Prior symptomatic stroke | 29 (21) | 47 (22) | 0.85 | 11 (14) | 35 (11) | 0.55 |
| Peripheral vascular disease | 14 (10) | 11 (5) | 0.07 | 5 (6) | 21 (7) | 1.0 |
| Aortic vascular disease | 6 (4) | 12 (6) | 0.61 | 7 (9) | 23 (8) | 0.64 |
| Atrial fibrillation/flutter‡ | 52 (37) | 98 (45) | 0.14 | 27 (34) | 165 (54) | 0.002 |
| VT/VF | 2 (1) | 10 (5) | 0.14 | 3 (4) | 16 (5) | 0.78 |
| Malignancy | 21 (15) | 35 (16) | 0.79 | 15 (19) | 47 (15) | 0.44 |
| COPD | 7 (5) | 17 (8) | 0.39 | 10 (13) | 29 (10) | 0.41 |
| Asthma | 2 (1) | 16 (7) | 0.01 | 5 (6) | 20 (7) | 1.0 |
| Liver cirrhosis (Child–Pugh B or C) | 2 (1) | 0 | 0.15 | 0 | 0 | – |
| Prior PCI | 36 (26) | 54 (25) | 0.84 | 22 (28) | 63 (21) | 0.17 |
| Prior CABG | 8 (6) | 16 (7) | 0.67 | 5 (6) | 22 (7) | 1.0 |
| Prior open heart surgery without CABG | 6 (4) | 16 (7) | 0.27 | 5 (6) | 22 (7) | 1.0 |
| Hemodynamic data on admission | ||||||
| Heart rate (beats/min) | 102±24 | 98±27 | 0.14 | 91±26 | 90±31 | 0.86 |
| SBP (mmHg) | 173±34 | 150±33 | <0.001 | 170±28 | 140±27 | <0.001 |
| SBP >140 mmHg†,‡ | 121 (86) | 118 (54) | <0.001 | 72 (91) | 130 (43) | <0.001 |
| DBP (mmHg) | 93±28 | 84±27 | <0.001 | 86±24 | 77±22 | 0.001 |
| Symptoms on admission | ||||||
| NYHA 3–4 | 136 (98) | 196 (90) | 0.005 | 73 (92) | 269 (88) | 0.41 |
| Orthopnea | 127 (91) | 169 (78) | 0.001 | 62 (78) | 181 (60) | 0.002 |
| Rale | 124 (89) | 173 (79) | 0.02 | 56 (71) | 146 (48) | <0.001 |
| Dyspnea on exertion | 138 (99) | 209 (96) | 0.10 | 77 (97) | 284 (93) | 0.27 |
| Jugular venous distention | 122 (88) | 172 (80) | 0.047 | 62 (78) | 202 (66) | 0.04 |
| Edema | 99 (71) | 153 (71) | 0.88 | 57 (72) | 224 (74) | 0.75 |
| Chest X-ray findings | ||||||
| Pleural effusion | 128 (91) | 201 (92) | 0.79 | 65 (82) | 262 (86) | 0.42 |
| Laboratory data on admission | ||||||
| Hemoglobin (mg/dL) | 11.9±2.6 | 11.4±2.5 | 0.047 | 11.9±2.1 | 11.7±2.4 | 0.44 |
| Anemia‡,§ | 83 (59) | 142 (65) | 0.26 | 52 (66) | 192 (63) | 0.64 |
| Blood urea nitrogen (mg/dL) | 22 (17–30) | 25 (18–36) | 0.11 | 23 (16–31) | 25 (16–36) | 0.25 |
| Creatinine (mg/dL) | 1.04 (0.79–1.55) |
1.06 (0.82–1.48) |
0.95 | 1.02 (0.75–1.41) |
1.06 (0.80–1.58) |
0.70 |
| eGFR (mL/min/1.73 m2) | 46.5 (31.1–64.3) |
45.9 (29.9–62.0) |
0.69 | 50.5 (37.5–61.2) |
45.3 (29.8–62.3) |
0.35 |
| eGFR <45 mL/min/1.73 m2†,‡ | 65 (46) | 102 (47) | 0.95 | 30 (38) | 150 (49) | 0.08 |
| Serum sodium (mmol/L) | 140 (137–142) |
139 (137–142) |
0.92 | 140 (137–142) |
140 (137–142) |
0.92 |
| Serum sodium <135 mmol/L‡ | 10 (7) | 26 (12) | 0.14 | 8 (10) | 47 (15) | 0.23 |
| Serum potassium (mmol/L) | 4.2 (3.7–4.7) | 4.3 (3.9–4.7) | 0.18 | 4.4 (4.1–4.7) | 4.3 (3.9–4.7) | 0.87 |
| γ-Glutamyl transpeptidase, U/L | 35 (18–66) | 32 (19–65) | 0.92 | 36 (18–68) | 40 (21–78) | 0.24 |
| Total bilirubin (mg/dL) | 0.7 (0.5–1.0) | 0.6 (0.4–0.9) | 0.05 | 0.7 (0.5–1.0) | 0.7 (0.5–1.1) | 0.12 |
| BNP (pg/mL) | 878 (540–1,617) |
721 (407–1,161) |
0.02 | 721 (512–1,360) |
686 (382–1,266) |
0.35 |
| BNP <742 pg/mL‡ | 56 (40) | 114 (52) | 0.03 | 41 (52) | 159 (52) | 0.93 |
| Echocardiographic parameters | ||||||
| LVEF (%) | 43 (33–54) | 46 (35–60) | 0.26 | 46 (35–60) | 49 (33–60) | 0.93 |
| LVEF <40%†,‡ | 55 (39) | 75 (35) | 0.37 | 26 (33) | 106 (35) | 0.81 |
| Moderate–severe mitral regurgitation | 37 (28) | 72 (37) | 0.10 | 16 (23) | 128 (45) | <0.001 |
| Moderate–severe aortic stenosis‡ | 19 (14) | 48 (22) | 0.046 | 8 (10) | 49 (16) | 0.22 |
| Initial therapy | ||||||
| Admission to coronary care unit | 102 (73) | 117 (54) | <0.001 | 38 (48) | 86 (28) | <0.001 |
| Renal replacement therapy | 4 (3) | 6 (3) | 1.0 | 0 | 3 (1) | 1.0 |
| Respiratory tract | ||||||
| Non-invasive PPV | 82 (59) | 96 (44) | 0.008 | 30 (38) | 54 (18) | <0.001 |
| Invasive PPV | 7 (5) | 4 (2) | 0.12 | 0 | 1 (0.3) | 1.0 |
| Infusion drugs | ||||||
| Furosemide | 132 (94) | 207 (95) | 0.81 | 73 (92) | 278 (91) | 0.72 |
| Nitroglycerin/Isosorbide dinitrate | 71 (51) | 44 (20) | <0.001 | 30 (38) | 33 (11) | <0.001 |
| Nicardipine | 44 (31) | 32 (15) | <0.001 | 19 (24) | 20 (7) | <0.001 |
| Dobutamine | 8 (6) | 25 (11) | 0.09 | 8 (10) | 38 (12) | 0.70 |
| Carperitide dose (μg/kg/min) | 0.03 (0.02–0.03) |
0.03 (0.02–0.03) |
||||
Data given as n (%), mean±SD, or median (IQR). †Potential independent variables selected for Cox proportional hazard models of all-cause death and rehospitalization for heart failure. ‡Potential independent variables selected for Cox proportional hazard models of a composite of all-cause death or rehospitalization for heart failure. §Defined according to the World Health Organization criteria: hemoglobin <12.0 g/dL in women and <13.0 g/dL in men. AHF, acute heart failure; BNP, brain natriuretic peptide; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PPV, positive pressure ventilation; SBP, systolic blood pressure; VF, ventricular fibrillation; VT, ventricular tachycardia.
Table 1 lists baseline patient characteristics according to carperitide status and stratified according to degree of pulmonary congestion. The admission blood pressure of the carperitide group was higher than that of the non-carperitide group, and the carperitide group had more symptoms caused by AHF than the non-carperitide group, irrespective of the degree of pulmonary congestion. There were no differences in age, renal function, or ejection fraction between the 2 groups, irrespective of the degree of pulmonary congestion.
Short-Term OutcomesTable 2 lists the short-term outcomes according to carperitide status and stratified according to degree of pulmonary congestion. The carperitide group had higher 24-h urine output than the non-carperitide group, irrespective of the degree of pulmonary congestion. In patients with moderate–severe pulmonary congestion, the carperitide group had significantly shorter days to decongestion on chest X-ray and significantly lower rates of remaining dyspnea on exertion and congestion on chest X-ray at discharge than the non-carperitide group. In patients with no–mild pulmonary congestion, there was no difference in HF symptoms or remaining congestion on chest X-ray at discharge between the 2 groups. In AHF patients with moderate–severe pulmonary congestion, ∆creatinine was not different between the 2 groups. In patients with no–mild pulmonary congestion, however, it was greater in the carperitide group than in the non-carperitide group. There was no difference in the rate of in-hospital death between the 2 groups, irrespective of the degree of pulmonary congestion.
| Carperitide group | Non-carperitide group | P-value | |
|---|---|---|---|
| Moderate–severe pulmonary congestion | n=140 | n=218 | |
| 24-h urine output (mL) | 2,750 (1,900–3,340) | 2,292 (1,705–3,100) | 0.006 |
| Time to decongestion on chest X-ray (days)† | 4.1±3.0 | 5.0±3.8 | 0.033 |
| In-hospital death | 6 (4.3) | 15 (6.9) | 0.36 |
| ΔCreatinine‡ | 0.09 (−0.06 to 0.36) | 0.06 (−0.08 to 0.24) | 0.18 |
| Symptoms at discharge | |||
| Dyspnea on exertion | 13 (9.8) | 35 (17.3) | 0.0536 |
| Peripheral edema | 11 (8.3) | 19 (9.5) | 0.71 |
| Fatigue | 7 (5.3) | 18 (8.9) | 0.29 |
| Congestion on chest X-ray at discharge | 2 (1.5) | 18 (9.0) | 0.004 |
| Pleural effusion on chest X-ray at discharge | 23 (17.2) | 46 (23.0) | 0.20 |
| No–mild pulmonary congestion | n=79 | n=305 | |
| 24-h urine output (mL) | 2,500 (1,753–3,715) | 2,180 (1,523–2,800) | 0.006 |
| In-hospital death | 2 (2.5) | 17 (5.6) | 0.39 |
| ΔCreatinine‡ | 0.12 (−0.13 to 0.33) | 0.04 (−0.12 to 0.17) | 0.014 |
| Symptoms at discharge | |||
| Dyspnea on exertion | 12 (15.6) | 44 (15.3) | 0.95 |
| Peripheral edema | 5 (6.5) | 38 (13.2) | 0.11 |
| Fatigue | 6 (7.8) | 34 (11.8) | 0.41 |
| Congestion on chest X-ray at discharge | 5 (6.6) | 15 (5.3) | 0.59 |
| Pleural effusion on chest X-ray at discharge | 17 (22.4) | 64 (22.5) | 0.98 |
Data given as n (%), mean±SD, or median (IQR). †Decongestion confirmed on chest X-ray: carperitide group, n=111 (79%); non-carperitide group, 172 patients (79%). ‡Change from admission to discharge. AHF, acute heart failure.
In AHF patients with moderate–severe pulmonary congestion, the cumulative 180-day incidences of rehospitalization for HF and of a composite of all-cause death or rehospitalization for HF were significantly lower in the carperitide group than in the non-carperitide group (Table 3; Figure 2B,C). In patients with no–mild pulmonary congestion, the cumulative 180-day incidence of rehospitalization for HF was significantly higher in the carperitide group than in the non-carperitide group (Table 3; Figure 2B). The results of the landmark analysis of patients who were discharged alive were similar to those of the primary analysis (Figure S2).
| Carperitide group: patients with ≥1 event |
Non-carperitide group: patients with ≥1 event |
Unadjusted HR (95% CI) |
P-value | Adjusted HR (95% CI) |
P-value | |
|---|---|---|---|---|---|---|
| Cumulative 180-day incidence (%) |
Cumulative 180-day incidence (%) |
|||||
| Moderate–severe pulmonary congestion |
n=140 | n=218 | ||||
| All-cause death | 22 (6.0) | 40 (13.4) | 0.76 (0.45–1.27) | 0.31 | 0.86 (0.49–1.49) | 0.60 |
| Cardiovascular death | 12 (4.6) | 25 (9.9) | 0.69 (0.33–1.34) | 0.28 | – | – |
| Sudden death | 3 (0) | 1 (0.6) | 4.15 (0.53–84.15) | 0.18 | – | – |
| Non-cardiovascular death | 10 (1.4) | 15 (3.8) | 0.88 (0.38–1.96) | 0.76 | – | – |
| Rehospitalization for HF | 21 (14.1) | 51 (20.6) | 0.58 (0.34–0.96) | 0.03 | 0.50 (0.29–0.84) | 0.009 |
| Composite of all-cause death or rehospitalization for HF |
40 (18.6) | 82 (29.6) | 0.67 (0.45–0.97) | 0.03 | 0.62 (0.41–0.93) | 0.02 |
| No–mild pulmonary congestion | n=79 | n=305 | ||||
| All-cause death | 13 (8.5) | 52 (12.6) | 0.91 (0.48–1.63) | 0.77 | 1.42 (0.67–2.91) | 0.35 |
| Cardiovascular death | 9 (7.0) | 31 (8.2) | 1.06 (0.47–2.13) | 0.88 | – | – |
| Sudden death | 1 (0) | 7 (0.4) | 0.48 (0.03–2.71) | 0.45 | – | – |
| Non-cardiovascular death | 4 (1.6) | 21 (4.8) | 0.70 (0.20–1.84) | 0.49 | – | – |
| Rehospitalization for HF | 21 (22.9) | 47 (14.6) | 1.77 (1.03–2.92) | 0.04 | 2.66 (1.43–4.89) | 0.002 |
| Composite of all-cause death or rehospitalization for HF |
27 (27.4) | 87 (23.9) | 1.20 (0.77–1.83) | 0.41 | 1.80 (1.06–3.01) | 0.03 |
†The number of patients with ≥1 event was counted through the entire follow-up period, while the cumulative incidence was truncated on the 180th day. Follow-up was commenced on the day of admission for heart failure. AHF, acute heart failure; HF, heart failure.
Cumulative incidence of (A) all-cause death, (B) rehospitalization for heart failure (HF), and (C) a composite of all-cause death or rehospitalization for HF in acute HF patients with (Left) moderate–severe and (Right) no–mild congestion on chest X-ray according to carperitide status.
In the assessment of the short-term outcome measures, the results of the sensitivity analysis were similar to those of the primary analysis, irrespective of the degree of pulmonary congestion (Table 4). On assessment of the long-term outcome measures, the sensitivity analysis results were similar to those of the primary analysis in AHF patients with moderate–severe pulmonary congestion, but were significantly different in AHF patients with no–mild pulmonary congestion (Table 5; Figure 3).
| Carperitide group | Non-carperitide group | P-value | |
|---|---|---|---|
| Moderate–severe pulmonary congestion | n=98 | n=98 | |
| Time to decongestion on chest X-ray (days)† | 4.5±3.6 | 4.7±4.4 | 0.65 |
| In-hospital death | 5 (5.1) | 2 (2.0) | 0.44 |
| ΔCreatinine‡ | 0.12 (−0.06 to 0.36) | 0.10 (−0.03 to 0.38) | 0.83 |
| Symptoms at discharge | |||
| Dyspnea on exertion | 7 (7.6) | 16 (17.0) | 0.07 |
| Peripheral edema | 8 (8.7) | 9 (9.6) | 1.0 |
| Fatigue | 5 (5.4) | 12 (8.5) | 0.57 |
| Congestion on chest X-ray at discharge | 1 (1.1) | 15 (15.8) | <0.001 |
| Pleural effusion on chest X-ray at discharge | 14 (15.1) | 16 (16.8) | 0.74 |
| No–mild pulmonary congestion | n=54 | n=54 | |
| In-hospital death | 2 (3.7) | 4 (7.4) | 0.68 |
| ΔCreatinine‡ | 0.14 (−0.13 to 0.35) | 0.13 (−0.15 to 0.23) | 0.22 |
| Symptoms at discharge | |||
| Dyspnea on exertion | 7 (13.5) | 7 (14.0) | 1.0 |
| Peripheral edema | 5 (9.6) | 5 (10.0) | 1.0 |
| Fatigue | 4 (7.7) | 8 (16.0) | 0.23 |
| Congestion on chest X-ray at discharge | 4 (7.7) | 1 (2.0) | 0.36 |
| Pleural effusion on chest X-ray at discharge | 13 (25.0) | 11 (22.0) | 0.72 |
†Decongestion confirmed on chest X-ray: carperitide group, n=73 (74%); non-carperitide group, 77 patients (79%). ‡Change from admission to discharge. AHF, acute heart failure.
| Carperitide group: patients with ≥1 event |
Non-carperitide group: patients with ≥1 event |
HR (95% CI) | P-value | |
|---|---|---|---|---|
| Cumulative 180-day incidence (%) |
Cumulative 180-day incidence (%) |
|||
| Moderate–severe pulmonary congestion | n=98 | n=98 | ||
| All-cause death | 14 (5.2) | 12 (8.5) | 0.84 (0.38–1.87) | 0.67 |
| Rehospitalization for HF | 12 (10.3) | 20 (17.5) | 0.49 (0.23–0.9995) | 0.0499 |
| Composite of all-cause death or rehospitalization for HF |
25 (15.1) | 31 (23.6) | 0.61 (0.35–1.04) | 0.07 |
| No–mild pulmonary congestion | n=54 | n=54 | ||
| All-cause death | 8 (8.2) | 12 (12.9) | 0.43 (0.16–1.09) | 0.08 |
| Rehospitalization for HF | 14 (20.6) | 10 (22.7) | 1.27 (0.57–2.96) | 0.56 |
| Composite of all-cause death or rehospitalization for HF |
18 (25.6) | 20 (33.3) | 0.80 (0.42–1.51) | 0.48 |
†The number of patients with ≥1 event was counted through the entire follow-up period, while the cumulative incidence was truncated on the 180th day. Follow-up was commenced on the day of admission for heart failure. AHF, acute heart failure; HF, heart failure.
Cumulative incidence of (A) all-cause death, (B) rehospitalization for heart failure (HF), and (C) a composite of all-cause death or rehospitalization for HF in a propensity score-matched cohort of acute HF patients with (Left) moderate–severe and (Right) no–mild congestion on chest X-ray according to carperitide status.
The main findings of this study are as follows: (1) in AHF patients with moderate–severe pulmonary congestion, carperitide can be associated with more effective decongestion in the short term and better prognosis in the long term; (2) in AHF patients with no–mild pulmonary congestion, it is not associated with better clinical outcomes; and (3) using the present protocol, carperitide did not increase the rate of in-hospital death, irrespective of the degree of pulmonary congestion.
This study was conducted on the basis of the hypothesis that carperitide might be associated with effective decongestion in AHF patients with moderate–severe pulmonary congestion by promoting diuresis and vasodilatation.
In countries outside Japan, nesiritide, a synthetic brain natriuretic peptide, is used in the management of AHF for its arterial and venous vasodilatory properties that reduce preload and afterload. The efficacy of nesiritide is similar to that of carperitide. In the Vasodilation in the Management of Acute CHF (VMAC) study that compared the efficacy and safety of nesiritide with those of nitroglycerin, nesiritide significantly reduced the pulmonary capillary wedge pressure (PCWP) in comparison with nitroglycerin.8 AHF patients with pulmonary congestion often have elevated PCWP, and it is possible that carperitide improves hemodynamic function and congestion in those patients effectively. In addition, the fact that carperitide shortens the time to decongestion might be associated with reduction in HF symptoms remaining at discharge.
The persistence of congestion during hospitalization is an important risk factor.9 In AHF patients with moderate–severe pulmonary congestion, carperitide seems to be able to shorten the time to decongestion and reduce HF symptoms remaining at discharge in the short term and lead to better prognosis in the long term. One possibility is that the renal protective effect, as reported in previous studies,3,10 may have improved the long-term prognosis, but it was not clarified in this study.
In AHF patients with no–mild pulmonary congestion, carperitide may increase admission for HF, but confirming this is difficult because of the different results between the primary and sensitivity analyses. The increase in creatinine during hospitalization was greater in the carperitide group than in the non-carperitide group, which may have negatively affected the long-term prognosis of the carperitide group. We speculated that decreased blood pressure due to carperitide’s vasodilator effect or dehydration due to carperitide’s diuretic effect may have negatively affected the carperitide group’s renal function on the basis of a previous report showing that hypotension in AHF patients receiving carperitide leads to renal dysfunction.11
Hypotension is a poor prognostic factor in AHF patients.12,13 Also, hypotension is one of the adverse events of carperitide treatment in AHF patients. In the present study, contradicting a recent study,5 carperitide did not increase the rate of in-hospital death, irrespective of the degree of pulmonary congestion, which may have reflected the differences in the protocols between the 2 studies. Based on the Kurashiki Central Hospital protocol, carperitide will be reduced in amount or discontinued to prevent poor outcome when the blood pressure falls or the urine output decreases in volume due to decreased blood pressure.
Study LimitationsThis study has 2 major limitations. One is that its observational study design was prone to inherent bias. This is because patients with higher admission blood pressure and more AHF symptoms tend to receive carperitide. In addition, we could not examine whether the duration of carperitide treatment had influenced clinical outcome. The other is that the number of study patients was too small to enable elucidation of the effects of carperitide in detail. Further prospective studies with a larger volume are awaited.
Accordingly, the present statistical analysis and results were affected by the aforementioned limitations. In the assessment of the short-term outcome measures, the number of events was too small to perform multivariable analysis. We therefore developed propensity scores for carperitide treatment at the time of baseline assessment and conducted a sensitivity analysis using a matched cohort of the carperitide and non-carperitide groups based on the propensity scores. The results of the sensitivity analysis were similar to those of the primary analysis. In the assessment of the long-term outcome measures, having performed an extensive multivariable adjustment, we could not deny the possibility of unmeasured confounders and selection bias. The results of the sensitivity analysis were similar to those of the primary analysis in patients with moderate–severe pulmonary congestion, but were significantly different in patients with no–mild pulmonary congestion. Consequently, patients with moderate–severe pulmonary congestion had better prognosis. Patients with no–mild pulmonary congestion showed no improvement, but the appropriateness of this result remains unclear.
In the treatment of AHF with moderate–severe pulmonary congestion, carperitide is associated with more effective decongestion in the short term and better prognosis in the long term. Selecting patients with an appropriate clinical condition and setting a safety protocol for carperitide are key factors in the successful treatment of AHF.
We are grateful to Miho Kobayashi for writing assistance.
The authors declare no conflicts of interest.
Supplementary File 1
Figure S1. Propensity score distribution according to carperitide status in acute heart failure patients with (Left) moderate–severe congestion and (Right) no–mild congestion on chest X-ray.
Figure S2. Cumulative incidence of (A) all-cause death, (B) rehospitalization for heart failure (HF), and (C) a composite of all-cause death or rehospitalization for HF in acute HF patients with (Left) moderate–severe and (Right) no–mild congestion on chest X-ray according to carperitide status, who were discharged alive: landmark analysis.
Table S1. Pulmonary congestion grading
Table S2. Propensity score-matched cohort: AHF patient characteristics
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-18-0057
