Clinical Assessment of Hypoperfusion in Acute Heart Failure

– Evergreen or Antique? –

Abstract

Background: Cold hemodynamic profile assessed on physical examination predicts survival, although it has low specificity and low reproducibility. We herein propose a new cold profile definition (Cold Modified 2014), including renal and hepatic damage. The aim of the study was to evaluate the additional prognostic value of clinical and laboratory identification of hypoperfusion over hypotension in the setting of advanced acute heart failure (AHF).

Methods and Results: After preliminary analysis on derivation cohort, we studied 223 consecutive NYHA III–IV patients admitted with AHF requiring intensive care. Cold Modified 2014 definition included non-invasive hemodynamic assessment, renal and hepatic injury. Primary endpoint was a composite of cardiac death, urgent heart transplantation and mechanical circulatory support at 6 months. In the validation cohort (age, 60.5±12.8 years; ejection fraction 25.6±8.2%, systolic blood pressure [SBP] 104.3±26.1 mmHg) 77 reached the composite endpoint. Among SBP, ADHERE model, cold profile at admission and INTERMACS profile at 48 h, cold profile had the best diagnostic accuracy. On multivariate analysis only cold profile and INTERMACS predicted events, while SBP <115 mmHg and high risk on ADHERE did not. Cold Modified 2014 was more accurate than the old definition. Net reclassification improvement for Cold Modified 2014 over the old definition was 25.8%.

Conclusions: This prospective study demonstrated the additional prognostic role of hypoperfusion assessment over hypotension in patients with AHF. Cold Modified 2014 improved risk stratification in advanced AHF patients.

Clinical assessment and risk stratification in advanced acute heart failure (AHF) patients should facilitate proper and timely decision making regarding medical treatment, mechanical circulatory support (MCS) or urgent transplantation. Previous studies showed that clinical Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile is a determinant of prognosis both after left ventricular assist device (LVAD) and heart transplantation.^1,2 Nevertheless evaluation of INTERMACS profile in the acute setting is challenging due to the sudden changes of clinical status and due to the subjectivity of the evaluation.

Nohria et al showed that clinical hypoperfusion (cold hemodynamic profile) assessed on physical examination predicts survival in patient with AHF,³ although this definition had a low specificity in the prediction of low cardiac output and was affected by high interobserver variability.⁴

Afterwards Stevenson added new criteria of hypoperfusion such as worsening renal function (WRF) and hyponatremia,⁵ given that both are independent prognostic tools.^6–9 The additional prognostic value of these new parameters in the cold profile definition, however, has not been evaluated as yet. In contrast, the ADHERE risk tree model and new guidelines recently stressed the pivotal role of hypotension over hypoperfusion in risk stratification and treatment of AHF patients.^10,11

We tried to improve the Nohria et al cold definition with the addition of more specific and reproducible signs of hypoperfusion. Therefore, we selected laboratory parameters known to be associated with low cardiac output and with worse prognosis: we identified WRF,¹² hyperbilirubinemia (cut-off of 1.2 mg/dl, from Shinagawa et al¹³) and hyponatremia (with a cut-off of 130 mEq/L from the ESCAPE risk model⁷). These three items were included in a new cold definition, the Cold Modified 2014; cut-offs for this definition were predefined according to previous literature and confirmed using a derivation cohort.

The aim of this study was therefore to assess whether the clinical evaluation of hypoperfusion outperforms hypotension in the risk stratification. Moreover we proposed and validated the new definition of cold profile and compared it with the older definitions.

Methods

Derivation Cohort

We performed a preliminary analysis on a derivation cohort of advanced AHF patients admitted to the Intensive Cardiac Care Unit (ICCU) at Città della Salute e della Scienza University Hospital of Turin, Italy, between June and December 2010. Primary endpoint was a composite of cardiac death, urgent (UNOS status 1) heart transplantation and urgent (INTERMACS ≤3) MCS (extracorporeal membrane oxygenation [ECMO], or LVAD) implantation within 180 days from index hospitalization. The derivation cohort consisted of 50 patients, aged 61.2±11.6 years old, with ejection fraction (EF) 23.6±12.1% and systolic blood pressure (SBP) 86.2±26.2 mmHg. In the derivation cohort, 66% of patients had sodium <135 mEq/L, mean sodium was 131.1±6.4 mEq/L and the median was 131.5 mEq/L. Cold Modified 2014 was superior to Nohria et al 2003³ in predicting the primary endpoint (receiver operating characteristic [ROC] analysis: area under the curve [AUC], 0.79±0.07 vs. 0.68±0.8; Cox regression analysis: hazard ratio [HR], 8.9; 95% confidence interval [CI]: 2.5–31 vs. HR, 3.4; 95% CI: 1.3–8.8).

Subjects

We prospectively screened consecutive patients admitted to the ICCU for AHF between December 2011 and December 2013. Inclusion criteria were: age ≥18 years; signs or symptoms of AHF as primary cause of admission; New York Heart Association (NYHA) functional class III–IV; EF at admission <35%. Exclusion criteria were overt cardiogenic shock (INTERMACS 1) and the presence of a correctable causal factor of AHF (such as acute coronary syndrome, myocarditis, acute pulmonary embolism, rhythm disorders, etc). We screened 293 patients; among them 223 patients met the inclusion criteria.

The present study conformed with the principles outlined in the Declaration of Helsinki and was approved by the local institutional review boards; patients gave written informed consent.

Clinical Evaluation

At admission all patients underwent physical examination, including evaluation of congestion and perfusion state according to the literature,¹⁴ and laboratory testing.

Clinical evaluation included risk stratification with the ADHERE risk model,⁵ INTERMACS profile¹⁵ at 48 h, grading of congestion and identification of hypoperfusion (cold profile). The presence of congestion was assessed and graded according to a modified model from the ESC statement:¹⁴ a composite score ≥14/18 identified patients with severe congestion. Cold profile was identified according to predefined criteria, given in the following section.

WRF was defined as an increase of serum creatinine at 48 h from admission ≥0.3 mg/dl (26.5 μmol/L) or ≥25% or oliguria³ (urine output <0.5 ml·kg^–1·h^–1 for ≥6 h)¹² once, excluding aggressive decongestion or overtreatment with diuretics.

Assessment of Cold Profiles

On the basis of clinical evaluation and laboratory tests all patients were classified as cold or not cold according to three different definitions of cold profile. Patients who fulfilled the relevant criteria were considered “cold” for the specific definition.

The 3 definitions were as follows.

(1) Nohria et al 2003: patients were considered as cold when they had at least one of the following clinical criteria: (i) cold extremities or diaphoresis; (ii) alternans or parvus pulse; (iii) altered mental status; and (iv) proportional differential pressure <25%.³

(2) Stevenson 2005: patients were considered as cold when they had at least one of the following clinical criteria: (i) clinical criteria (as listed for Nohria et al 2003³); (ii) angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) intolerance; and (iii) WRF.⁵

(3) Cold Modified 2014: patients were considered cold when they presented with at least two different clusters: (i) hemodynamic cluster, showing at least one of the following: clinical criteria (as listed for Nohria et al 2003³), ACEI/ARB intolerance, serum sodium <130 mmol/L; (ii) renal cluster: WRF; or (iii) hepatic cluster: total bilirubin ≥1.2 mg/dl (once other causes of hyperbilirubinemia were excluded).

Endpoints

Patients were followed for at least 6 months after the index admission. The primary endpoint was a composite of cardiac death, urgent (UNOS status 1) heart transplantation and urgent (INTERMACS ≤3) MCS (ECMO or LVAD) implantation within 180 days from index hospitalization.

Secondary endpoints were: (1) all-cause mortality within 180 days; and (2) worsening HF during index hospitalization.¹⁶

Predefined Risk Factors

The predefined parameters at admission studied as risk factors for cardiac events were: ADHERE risk evaluation, cold presentation,³ composite congestion score ≥14/18,¹⁴ SBP <115 mmHg¹³ and SBP as continuous variable, N-terminal pro-B-type natriuretic peptide >8,229 pg/ml,¹⁷ Estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula <30 ml·min^–1·1.73 m^–2,¹ blood urea nitrogen (BUN) >90 mg/dl,⁷ cardiac injury (baseline troponin T >0.03 ng/ml),³ Na <130 mmol/L, hepatic injury (total bilirubin ≥1.2 mg/dl once other causes of hyperbilirubinemia were excluded²), EF,¹⁸ estimated right atrial pressure ≥20 mmHg, tricuspid annular plane systolic excursion (TAPSE) ≤14 mm,¹⁸ and simplified right ventricular contraction-pressure index <400 mm·mmHg according to the previous definition (TAPSE×RV-RA gradient).¹⁹

Treatment Protocol

Treatment followed ESC Guideline recommendations¹¹ and the Italian consensus on inotropes.²⁰

First-line therapy included nitroprusside and i.v. diuretics, dopamine or dobutamine <2 γ·kg^–1·min^–1 for patients with SBP 90–100 mmHg at admission or need for high doses of diuretics (i.v. furosemide ≥240 mg/day). Patients without acute pulmonary edema and without severe tissue hypoperfusion or inotropic dependence received an unaltered β-blockers dosage. Inotropic support was established if one of the following occurred: cardiogenic shock, hypoperfusion according to clinician judgment, inadequate response at 48 h to optimized first-line treatment. Levosimendan was recommended in cold patients on β-blockers and/or ischemic etiology of HF with SBP ≥90 mmHg. Patients with cardiogenic shock were treated with low-dose epinephrine²¹ and, when indicated, with temporary cardiac support (intra-aortic balloon pump or MCS). Renal replacement treatment was indicated in patients with persistence of congestion and reduced response to diuretic (absence of weight reduction and/or sodium excretion <30 mmol/L) despite mean arterial pressure ≥65 mmHg and optimal medical therapy including high-dose loop diuretics and sequential nephron blockade.^22,23

Statistical Analysis

Categorical variables are reported as n (%), while continuous variables are given as mean±SD. Correlation between variables and different cold definitions was tested using cross-tabulation tables with Pearson chi-squared test and by one-way ANOVA for categorical and continuous variables, respectively.

The ability to predict events for each definition of cold profile was tested using ROC curves. AUC >0.7 was considered fair accuracy.

Kaplan-Meier curves were used to measure freedom from adverse clinical events. Univariate Cox regression analysis was used to assess correlation of predefined parameters with the event. All variables with P<0.2 on univariate analysis were included in the multivariate Cox regression analysis.

The effects of reclassification using Cold Modified 2014 were assessed with net reclassification improvement (NRI). This approach separately analyzed the reclassification of persons who met the primary endpoint from cardiovascular causes and those who did not.²⁴

Two-sided P<0.05 was considered statistically significant; all analysis was performed with SPSS 20.0 (IBM, Armonk, NY, USA).

Results

Subject Characteristics and Outcomes

We enrolled 223 patients: mean age was 60.5±12.8 years, 75.3% were male, the most common underlying disorder was ischemic cardiomyopathy and 76.7% had advanced HF.²⁵ At admission mean SBP was 104.3 mmHg, mean BUN was 84.0 mg/dl. Other characteristic are listed in Table 1.

Table 1. Baseline Characteristics

	Total (n=223)	Primary event (n=77)	No primary event (n=146)	P-value
Clinical characteristics
Age (years)	60.5±12.8	56.3±14.3	61.8±11.7	0.005
Male	168 (75.3)	61 (79.2)	107 (73.3)	0.616
Ischemic etiology	123 (55.2)	31 (40.3)	66 (45.2)	0.475
Advanced HF	171 (76.7)	70 (90.1)	101 (69.2)	<0.001
SBP (mmHg)	104.3±26.1	90.1±20.1	108.3±26.3	<0.001
Heart rate (beats/min)	87.6±17.5	89.3±16.2	87.1±18.0	0.438
Composite congestion score ≥14/18	48 (21.5)	24 (31.2)	24 (16.4)	0.025
INTERMACS profile <5	168 (75.3)	70 (90.1)	98 (67.1)	<0.001
AF	100 (44.8)	38 (49.4)	61 (41.8)	0.392
Laboratory data
Creatinine (md/dl)	1.55±0.91	1.67±1.10	1.54±0.82	0.373
eGFR by MDRD (ml·min−1·1.73 m−2)	55.8±26.3	58.0±31.3	54.8±24.7	0.459
BUN (mg/dl)	84.0±55.6	90.1±57.7	82.4±55.2	0.428
Serum sodium (mmol/L)	134.4±7.3	132.0±8.4	135.1±6.8	0.009
Serum bilirubin (mg/dl)	1.35±0.89	1.8±1.1	1.1±0.7	<0.001
NT-proBNP at 24 h (pg/ml)	8,998.2±5,618.2	11,151.4±5,551.8	7,899.4±4,784.6	0.042
Troponin T (ng/ml)	0.082±0.047	0.150±0.065	0.102±0.032	0.470
Echo-Doppler parameters
Ejection fraction (%)	25.6±8.2	22.9±12.4	26.3±12.1	0.097
LVEDD (mm)	67.4±14.1	67.5±16.7	67.5±13.3	0.987
Deceleration time (ms)	122.±37.0	116.4±43.4	127.0±30.9	0.173
Average E/e’ ratio	18.75±7.7	18.7±7.1	18.5±8.0	0.864
eRAP (mmHg)	14.9±4.2	16.6±4.5	14.0±5.5	0.001
sPAP (mmHg)	51.2±13.9	51.8±14.7	50.7±13.5	0.623
TAPSE (mm)	14.9±4.2	12.4±4.8	14.2±6.2	0.064
sRVCPI (mm·mmHg)	513.5±283.7	407.8±201.4	566.2±295.1	0.001

Data given as mean±SD or n (%). AF, atrial fibrillation; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; eRAP, estimated right atrial pressure; HF, heart failure; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; LVEDD, left ventricular end-diastolic diameter; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SBP, systolic blood pressure; sPAP, systolic pulmonary artery pressure; sRVCPI, simplified right ventricular contraction-pressure index; TAPSE, tricuspid annular plane systolic excursion.

At 6 months 77 patients (34.5%) met the primary composite outcome of cardiac death, urgent transplantation or urgent LVAD implantation. Patients with events had more advanced HF, lower SBP, lower sodium, higher bilirubin and more impaired RV function (Table 1).

Death for any cause occurred in 41 patients (18.4%). Worsening HF during index hospitalization occurred in 103 patients (46.2%). During 6-month follow-up 2 patients underwent elective transplantation and 3 underwent elective LVAD implantation.

Predefined Risk Factors and Primary Endpoint

On univariate analysis several known predictors of primary endpoint were significant in Kaplan-Meier analysis (Table 2). On multivariate analysis only WRF (HR, 2.65; P=0.001) and serum bilirubin (HR, 2.39; P=0.001) significantly predicted events. Low serum sodium and ACEI intolerance showed a trend but did not reach significance.

Table 2. Predictors of Primary Composite Endpoint^† at 6 Months

Variables	Univariate analysis			Multivariate analysis
	HR	(95% CI)	P-value	HR	(95% CI)	P-value
Ischemic cardiomyopathy	0.83	0.52–1.32	0.437	–	–	–
ACEI intolerance	2.66	1.28–5.54	0.009	2.39	0.93–6.13	0.069
Heart rate (beats/min)	1.008	0.99–1.02	0.214	–	–	–
Differential pulse pressure <25%	0.77	0.34–1.79	0.567	–	–	–
SBP <115 mmHg	3.10	1.64–5.89	0.001	1.34	0.64–2.80	0.441
WRF at 48 h	2.78	1.76–4.38	0.000	2.65	1.51–4.69	0.001
Serum sodium <130 mmol/L	2.22	1.38–3.57	0.001	1.66	0.94–2.91	0.080
BUN >90 mg/dl	2.04	1.29–3.21	0.002	1.18	0.66–2.12	0.581
Serum bilirubin ≥1.2 mg/dl	2.67	1.68–4.27	0.000	2.39	1.40–4.10	0.001
NT-proBNP >8,229 pg/ml	1.64	1.04–2.66	0.033	1.00	0.57–1.72	0.985
Troponin T >0.03 ng/ml	1.74	1.00–2.88	0.047	1.19	0.67–2.08	0.544
Ejection fraction <20%	1.58	0.98–2.53	0.060	1.20	0.69–2.09	0.507
TAPSE ≤14 mm	1.67	1.04–2.67	0.033	1.46	0.85–2.52	0.171

^†Mortality plus urgent transplantation plus urgent left ventricular assist device implantation. ACEI, angiotensin-converting enzyme inhibitor; CI, confidence interval; HR, hazard ratio; WRF, worsening renal function. Other abbreviations as in Table 1.

Hypotension vs. Hypoperfusion for Prediction of Events

The SBP at admission was <115 mmHg in 146 patients; 65 patients of 146 (44.5%) reached the primary endpoint.

According to ADHERE risk model 33 patients were classified as low risk, 179 were classified at intermediate risk, while 11 were at high risk. Among the high-risk patients 7 (63.6%) met the primary endpoint.

At admission 38 were classified as cold according to Nohria et al 2003,³ 98 were classified as cold according to Stevenson 2005⁵ and 66 were classified as cold according to Cold Modified 2014. Among them 20 (52.6%), 47 (48.0%) and 42 (63.6%) met the primary composite endpoint, respectively. All cold patients, independently from the definition used, had SBP <115 mmHg.

At 48 h 60 patients were evaluated as having INTERMACS profile 3 or lower. Thirty-eight of them (63.3%) met the primary composite endpoint.

The diagnostic accuracy of SBP (as both a continuous variable and as SBP <115 mmHg), of the ADHERE risk model (as both a continuous variable and as low/intermediate risk vs. high risk), of cold profile at admission and of INTERMACS profile at 48 h was calculated for the prediction of the primary endpoint (Table 3A). Among parameters evaluated at admission, cold profile had the best diagnostic accuracy (AUC, 0.726; P<0.001).

Table 3. Prediction of Primary Event: Hypotension vs. Hypoperfusion

(A) ROC analysis for primary composite endpoint† at 6 months
	AUC	P-value	Sensitivity (%)	Specificity (%)
SBP (continuous variable)	0.659	<0.001	–	–
SBP <115 mmHg	0.632	0.001	84.4	41
ADHERE risk model (continuous variable: low, intermediate, high risk)	0.661	<0.001	–	–
ADHERE risk model: high risk	0.584	0.044	9.1	59.1
INTERMACS profile (continuous variable)	0.726	<0.001	–	–
INTERMACS profile ≤3	0.672	<0.001	48.7	25.3
Cold profile: Nohria et al 20033	0.577	0.054	26.8	88.7
Cold profile: Stevenson 20055	0.635	0.001	61.0	65.8
Cold profile: Cold Modified 2014	0.726	<0.001	57.3	87.9
(B) Predictors of primary composite endpoint†† at 6 months
Variables	Univariate analysis			Multivariate analysis
	HR	(95% CI)	P-value	HR	(95% CI)	P-value
SBP (HR per 10-mmHg decrease)	1.17	1.08–1.29	0.001	1.07	0.95–1.01	0.274
ADHERE risk model (HR per 1-level increase)	1.90	1.39–2.60	<0.001	1.22	0.85–1.73	0.266
INTERMACS profile at 48 h (HR per 1-level decrease)	2.18	1.66–2.86	<0.001	1.84	1.38–2.46	<0.001
Cold Modified 2014 profile at admission	4.27	(2.71–6.72)	<0.001	3.22	1.90–5.46	<0.001

^†Death, urgent transplantation, urgent MCS. ^††Mortality plus urgent transplantation plus urgent left ventricular assist device implantation. AUC, area under the curve; MCS, mechanical circulatory support; ROC, receiver operating characteristic. Other abbreviations as in Tables 1,2.

On Cox regression univariate analysis SBP <115 mmHg, high risk on ADHERE model, INTERMACS ≤3 and cold profile significantly predicted the primary endpoint. On multivariate analysis, however, only cold profile at admission and INTERMACS at 48 h predicted events (HR, 3.22 and 1.84, respectively; Table 3B), while SBP <115 mmHg and high risk on ADHERE model did not.

Assessment of Hypoperfusion

On ROC curve analysis the AUC for the primary composite endpoint was 0.577±0.041 (P=0.054), 0.635±0.039 (P=0.001) and 0.726±0.037 (P=0.000) for Nohria et al 2003,³ Stevenson 2005⁵ and Cold Modified 2014, respectively (Figure 1). Sensitivity was 26.8%, 61.0% and 57.3%, while specificity was 88.7%, 65.8% and 87.9% for Nohria et a 2003,³ Stevenson 2005⁵ and Cold Modified 2014, respectively (Table 4A).

Figure 1.

Area under the curve (AUC) of cold profile definitions for primary composite endpoint.

Table 4. Endpoints and Cold Definitions

(A) Endpoints vs. cold definition
	Total (n=223)	Nohria et al 20033		Stevenson 20055		Cold Modified 2014
		No cold (n=185)	Cold (n=38)	No cold (n=125)	Cold (n=98)	No cold (n=159)	Cold (n=64)
Composite of death, urgent HTx, urgent MCS at 6 months	77 (34.5)	57 (30.8)	20 (52.6)	30 (24.0)	47 (48.0)	35 (22.0)	42 (65.6)
All-cause mortality at 6 months	41 (18.4)	31 (16.8)	10 (26.3)	15 (12.0)	26 (26.5)	21 (13.2)	20 (31.2)
Worsening HF	103 (46.2)	81 (43.8)	21 (55.3)	42 (33.6)	60 (61.2)	60 (37.7)	42 (65.6)
(B) Kaplan-Meier analysis of cold definition
		Nohria et al 20033		Stevenson 20055		Cold Modified 2014
		HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value
Composite of cardiac death, urgent HTx, urgent MCS at 6 months		2.00 (1.20–3.33)	0.008	2.48 (1.57–3.94)	0.001	4.27 (2.71–6.72)	0.001
All-cause mortality at 6 months		1.85 (0.91–3.78)	0.109	2.69 (1.42–5.08)	0.002	3.21 (1.73–5.95)	0.001
Worsening HF		1.49 (0.74–3.02)	0.263	3.01 (1.73–5.25)	0.000	3.13 (1.70–5.80)	0.000

Data given as n (%). HTx, heart transplantation. Other abbreviations as in Tables 1–3.

The difference between AUC of Nohria et al 2003³ and Stevenson 2005⁵ was not significant (P=0.31), while Cold Modified 2014 had an AUC larger than Nohria et al 2003³ (P=0.007), and had a trend but did not reach significance when compared to Stevenson 2005⁵ (P=0.09).

Kaplan-Meier analysis confirmed that cold patients had a higher risk of events. HR for the primary composite endpoint were 2.00 (P=0.008), 2.48 (P=0.001), 4.27 (P=0.001) for Nohria et al 2003,³ Stevenson 2005⁵ and Cold Modified 2014, respectively (Figure 2). Stevenson 2005⁵ and Cold Modified 2014 predicted all-cause mortality and worsening HF, while Nohria et al 2003³ did not (Table 4B; Figure 3).

Figure 2.

Kaplan-Meier analysis of (A) Nohria et al 2003,³ (B) Stevenson 2005,⁵ and (C) Cold Modified 2014 for primary composite endpoint.

Figure 3.

Kaplan-Meier analysis of Cold Modified 2014 for all-cause death.

NRI is summarized in Table 5. In the 77 patients who met the primary endpoint, when compared with Nohria et al 2003³ and with Stevenson 2005,⁵ Cold Modified 2014 improved classification in 25 and in 9 patients, whereas it worsened it in 3 and 14, respectively. In the 146 patients who did not experience an event, Cold Modified reclassified 11 and 4 patients downward and 7 and 33 upward, when compared with Nohria et al 2003³ and Stevenson 2005,⁵ respectively. The NRI for Cold Modified 2014 over Nohria et al 2003³ was 25.8% (P<0.001) and over Stevenson 2005⁵ it was 13.6% (P=0.069).

Table 5. NRI Model With Cold Modified 2014

	Nohria et al 20033			Stevenson 20055
	No cold	Cold	Total	No cold	Cold	Total
Patients who met the primary endpoint
No Cold	32 (56.1) (−)	3 (15.0) (↓)	35	21 (70.0) (−)	14 (29.8) (↓)	35
Cold	25 (43.9) (↑)	17 (85.0) (−)	42	9 (30.0) (↑)	33 (70.2) (−)	42
Total no.	57	20	77	30	47	77
Patients who did not meet the primary endpoint
No Cold	117 (91.4) (−)	7 (38.8) (↑)	124	91 (95.8) (−)	33 (64.7) (↑)	124
Cold	11 (8.6) (↓)	11 (61.2) (−)	22	4 (4.2) (↓)	18 (35.3) (−)	22
Total no.	128	18	146	95	51	146
NRI (%)	25.8 (P<0.001)			13.6 (P=0.069)

↑, improvement in reclassification; −, no improvement in reclassification; ↓, failure in reclassification. NRI, net reclassification improvement.

Discussion

This prospective study demonstrated an improvement in prognostic accuracy when hypoperfusion assessment was used in patients with AHF compared with hypotension. The new definition of cold profile, Cold Modified 2014, had greater accuracy and better prognostic value than old definitions, as seen on ROC, Kaplan-Meier and NRI analysis.

Predefined Risk Factors of Primary Endpoint

The only predictors of events on multivariate analysis were WRF and serum bilirubin. Hyponatremia and ACEI intolerance showed a trend but did not reach statistical significance. These results confirm that both acute renal and hepatic damage, and hypotensive signs and symptoms likewise, are pivotal in risk assessment in AHF patients. As known, end-organ damage is associated with impaired cardiac output and systemic hypoperfusion.^26,27 Thus WRF and hepatic impairment, together with hypotension, are suitable features for cold profile, as markers of both compromised perfusion and worse outcome.

Hypotension vs. Hypoperfusion for Prediction of Events

The present study confirmed that, as shown with the ADHERE risk tree model, SBP at admission is a good predictor of outcome in AHF. In a population composed mainly of severe AHF requiring intensive care, however, SBP had high sensitivity but very low specificity in predicting primary events. Hence patients with SBP >115 mmHg could be confidently considered at low risk, but in contrast, SBP <115 mmHg was not sufficient in predicting events among patients at higher risk. From this point of view hypoperfusion (cold profile) was instead a good and very helpful predictor because it had a greater specificity than SBP and because its presence was restricted to the subgroup of patients with SBP <115 mmHg. Thus hypoperfusion could be the fittest parameter to stratify patients at higher risk.

Hypotension and ADHERE risk tree model still remain very useful tools to quickly and easily identify low-risk patients. They are pivotal in triage and in the emergency room in order to choose the proper intensity of treatment and place of care for each AHF patient.

In contrast, when evaluating patients with AHF, and in particular patients with severe HF, hypotension was not sufficient because of its poor specificity. Instead systematic evaluation of hypoperfusion identified those at higher risk. This could improve outcome in these patients because it could facilitate timely and appropriate medical treatment and provide appropriate patient selection for “extraordinary intervention” such as MCS or transplantation, thus improving cost-effectiveness in acute decompensated HF management.

INTERMACS profile is considered the gold standard for risk assessment in severe HF. It has good accuracy in predicting events and in predicting outcome after MCS implantation or transplantation. It is, however, a more subjective evaluation and is often difficult to assess accurately at admission, hence it is not able to predict, at admission, acute changes in hemodynamic state. Moreover, generation of a reliable INTERMACS profile assessment requires 48 h of careful clinical and laboratory evaluation. Nevertheless once correctly assessed INTERMACS profile is, together with cold profile, a good predictor of events.

In the present subjects cold profile at admission was superior to ADHERE risk model in predicting events. ADHERE failed to precisely stratify risk because the major proportion of patients were classified as intermediate risk. High-risk patients according to the ADHERE risk tree model have creatinine >2.75 mg/dl. Instead in the present population WRF was far more predictive than creatinine alone, given that many patients with renal impairment at 48 h had normal eGFR at admission.

Assessment of Hypoperfusion

Cold Modified 2014 had the highest accuracy and the better risk stratification, as shown on ROC curve analysis, NRI model and Kaplan-Meier analysis.

Cold diagnosis as a marker of compromised systemic perfusion is probably a continuum and not a yes/no feature, and this is why clinicians need a more accurate tool. We demonstrated that Cold Modified 2014 is the fittest, because it seems to be a good compromise between the high specificity but low sensitivity of Nohria et al 2003³ and the high sensitivity but low specificity of Stevenson 2005.⁵

The good accuracy obtained is probably the result of blending the high specificity but low sensitivity physical examination with the high sensitivity but low specificity laboratory testing.

In this study each cold definition was simple, objective and reproducible, because each was assessed using detailed criteria and not clinician experience. This is an advantage because Nohria et al did not require clinician assignment of clinical profile. This made their cold profile assessment highly subjective.

Moreover, the cold definition proposed by Stevenson in 2005 was based on solid evidence but until now it has never been validated. The present study confirmed the accuracy of that definition.

Cold Profile and Hypoperfusion

In the Nohria et al³ study cold patients had a not statistically significant trend to lower cardiac output.¹ The ESCAPE trial showed that pulmonary artery catheter-guided treatment did not affect overall mortality and hospitalization.²⁸ These data suggest that mere assessment of cardiac output (invasive or non-invasive) is not sufficient for risk stratification and tailoring of treatment.

In contrast, several studies demonstrated that end-organ damage is associated with worse prognosis. That condition reflects not only low cardiac output but also peripheral congestion, end-organ functional reserve, neurohormonal activation and inflammation. Therefore peripheral hypoperfusion as a result of the impairment of these mechanisms could be the most appropriate feature to improve therapy and prognosis.

Clinical Impact and Future Perspectives

It is well known that urgent transplantation may be associated with worse results compared with elective transplantation.¹ Moreover INTERMACS profile 1 and 2 patients have poorer survival than those who are less ill at the time of LVAD implantation, and have prolonged lengths of stay after LVAD implantation.²

Thus the success of a transplantation or MCS program depends as much on appropriate patient selection as it does on the technology implanted and the perioperative and long-term clinical management.

In this regard a simple parameter, more specific than simple hypotension, able to predict events earlier than overt cardiogenic shock, is needed.

Assessment of “subclinical hypoperfusion” could be the appropriate clue to facilitate timely selection of MCS candidates, thus avoiding late interventions that instead lead to worse outcome, longer hospitalization, lower quality of life and worse cost-effectiveness.

The efficacy of the new clinical profile in guiding medical treatment and patient selection has still to be evaluated. Issues remain as to whether a standardized clinical evaluation compared with a single physician judgment can improve treatment in high-risk patients and whether prompt treatment can improve the prognosis of cold profile patients.

Study Limitations

The major limitations of the study were the single-center design and the low number of patients enrolled.

Another issue is that, even if we included all comers with systolic AHF, the present population was highly characterized by severe HF because Città della Salute e della Scienza University Hospital of Turin is the regional reference center for LVAD implantation and heart transplantation. This is relevant because the present results might not apply to healthier HF patients.

Moreover the present population was different from the one used for the ADHERE risk tree model. This could explain why the ADHERE risk tree model was less effective and accurate in the present study; also, the ADHERE risk tree model evaluated a different endpoint (in-hospital mortality) and not events at 180 days.

It should be noted that, even if we constructed a cold profile definition that was more reproducible and objective than Stevenson 2005,⁵ it would still be dependent on clinician ability. This of course raises the issue of reproducibility at other centers.

Conclusions

Assessment of hypoperfusion has additional prognostic value compared with SBP in patients admitted for AHF. Cold Modified 2014, constructed as an association of clinical evaluation and end-organ damage, improved risk stratification when compared with previous definitions. This easy-to-use tool resulted in good prediction of short-term outcome in AHF patients because it identified patients who experienced worsening HF during the index hospitalization and those with poor outcome at 6 months.

Disclosures

There are no conflicts of interest.

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