Author + information
- Received March 1, 2016
- Revision received June 23, 2016
- Accepted June 23, 2016
- Published online November 1, 2016.
- Julio Núñez, MDa,∗ (, )
- Pau Llàcer, MDb,
- Vicente Bertomeu-González, MDc,
- Maria José Bosch, MDd,
- Pilar Merlos, MDe,
- Sergio García-Blas, MDa,
- Vicente Montagud, MDf,
- Vicent Bodí, MDa,
- Vicente Bertomeu-Martínez, MDc,
- Valle Pedrosa, MDe,
- Andrea Mendizábal, MDb,
- Alberto Cordero, MDc,
- Jorge Gallego, MDd,
- Patricia Palau, MDd,
- Gema Miñana, MDa,
- Enrique Santas, MDa,
- Salvador Morell, MDf,
- Angel Llàcer, MDa,
- Francisco J. Chorro, MDa,
- Juan Sanchis, MDa,
- Lorenzo Fácila, MDf,
- CHANCE-HF Investigators
- aServicio de Cardiología, Hospital Clínico Universitario, INCLIVA, Universitat de Valencia, Valencia, Spain
- bServicio de Medicina Interna, Hospital de Manises, Valencia, Spain
- cServicio de Cardiología, Hospital de San Juan, Alicante, Spain
- dServicio de Medicina Interna, Hospital de la Plana, Castellón, Spain
- eServicio de Cardiología, Hospital de Manises, Valencia, Spain
- fServicio de Cardiología, Hospital General Universitario de Valencia, Valencia, Spain
- ↵∗Reprint requests and correspondence:
Dr. Julio Núñez, Servicio de Cardiología, Hospital Clínico Universitario, Avenida Blasco Ibáñez 17, 46010 Valencia, Spain.
Objectives This study sought to evaluate the prognostic effect of carbohydrate antigen-125 (CA125)–guided therapy (CA125 strategy) versus standard of care (SOC) after a hospitalization for acute heart failure (AHF).
Background CA125 has emerged as a surrogate of fluid overload and inflammatory status in AHF. After an episode of AHF admission, elevated values of this marker at baseline as well as its longitudinal profile relate to adverse outcomes, making it a potential tool for treatment guiding.
Methods In a prospective multicenter randomized trial, 380 patients discharged for AHF and high CA125 were randomly assigned to the CA125 strategy (n = 187) or SOC (n = 193). The aim in the CA125 strategy was to reduce CA125 to ≤35 U/ml by up or down diuretic dose, enforcing the use of statins, and tightening patient monitoring. The primary endpoint was 1-year composite of death or AHF readmission. Treatment strategies were compared as a time to first event and longitudinally.
Results Patients allocated to the CA125 strategy were more frequently visited, and treated with ambulatory intravenous loop diuretics and statins. Likewise, doses of oral loop diuretics and aldosterone receptor blockers were more frequently modified. The CA125 strategy resulted in a significant reduction of the primary endpoint, whether evaluated as time to first event (66 events vs. 84 events; p = 0.017) or as recurrent events (85 events vs. 165 events; incidence rate ratio: 0.49; 95% confidence interval: 0.28 to 0.82; p = 0.008). The effect was driven by significantly reducing rehospitalizations but not mortality.
Conclusions The CA125 strategy was superior to the SOC in terms of reducing the risk of the composite of 1-year death or AHF readmission. This effect was mainly driven by significantly reducing the rate of rehospitalizations. (Carbohydrate Antigen-125-guided Therapy in Heart Failure [CHANCE-HF]; NCT02008110)
Morbidity and mortality rates remain very high after discharge from acute heart failure (AHF). Thus, development of new strategies aimed to decrease the risk during this vulnerable phase constitutes a research priority (1–3). This has led to a renewed interest in the use of biomarkers aimed at guiding the intensity of therapy. Indeed, some studies have shown that the trajectory of some biomarkers correlated with the course of the disease, which made them theoretically attractive for this purpose (4). However, it has been challenging to isolate their capacity to predict outcomes from their potential as a treatment-guiding tool. For instance, the efficacy of natriuretic peptide–guided strategies has revealed heterogeneous and conflicting results, particularly in highly comorbid and elderly subjects (5,6). There is growing evidence indicating that AHF may be a case mix of phenotypes contributing to the lack of well-defined evidenced-based therapies in this setting (7,8).
A great amount of evidence supports the role of sodium and fluid overload in AHF (9); nevertheless, its severity and organ distribution are largely heterogeneous (10,11). Fluid overload has been traditionally assessed through symptoms and signs, despite their limited accuracy (10,11). In recent years, carbohydrate antigen-125 (CA125), a widely available biomarker used for ovarian cancer monitoring (12), has emerged as a potential surrogate of fluid retention and inflammation activity in AHF (13). Published data has shown that high levels of this glycoprotein, which is present in up to two-thirds of patients hospitalized for AHF (13,14), correlate with the severity of AHF (13–15) and relate to morbidity and mortality (12). The potential role of this glycoprotein for monitoring and guiding post-discharge therapy has been suggested on the basis of the significant correlation between CA125 serum fluctuations with clinical outcomes (16–18), and response to loop diuretics and statin therapy (19,20).
With this rationale in mind, we designed this randomized multicenter clinical trial with the aim to evaluate the role of CA125 as a guiding tool strategy for patients recently discharged for AHF.
Study design and oversight
This is an investigator-initiated, multicenter, open-label, randomized controlled trial conducted from December 7, 2011, to July 17, 2014, in 5 academic centers in Spain. Informed consent was obtained from all patients or their nominated representative. The Institutional Review Board of each center and Agencia Española de Medicamentos y Productos Sanitarios approved the study. The study design was published previously (21). The trial was overseen by an independent data and safety monitoring board. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All analyses were performed by an independent company (CLINSTATS LLC, Reading, Pennsylvania).
Candidate patients were selected from a cohort of patients recently discharged for AHF. Inclusion and exclusion criteria for the trial are detailed in Online File 1. Briefly, the trial included patients with at least 1 episode of AHF in the last 180 days, New York Heart Association functional class ≥II at the moment of enrollment, CA125 >35 U/ml, and either echocardiographic evidence of a structural or functional abnormality of the heart congruent with heart failure (HF) diagnosis or elevation of natriuretic peptides (N-terminal pro–B-type natriuretic peptide [NT-proBNP] >1,000 pg/ml or B-type natriuretic peptide [BNP] >100 pg/ml), or both.
Trained physicians enrolled participants at each site. After providing the informed consent, patients were randomly assigned, with a remote, web-based computer-generated block randomization procedure in a 1:1 ratio, to either the CA125 strategy or standard of care (SOC). Patients, outcomes evaluators, and personnel involved in data management were masked to group assignment.
All patients were followed up in the outpatient HF clinics of each center with pre-specified visits at 1, 6, and 12 months after randomization. Additional outpatient visits were permitted in both arms at the discretion of the physician in charge of the patient. In all pre-specified visits, a sample of blood for standard laboratory testing and CA125 measurement (Elecsys CA125 II assay, Roche Diagnostics, Basel, Switzerland) was obtained. CA125 results were blinded to investigators and patients belonging to the SOC arm.
Patients allocated to SOC were treated following standard guidelines regarding the use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor antagonists (ARB), beta-blockers, aldosterone antagonists, ivabradine, statins, diuretics, and other treatments such as anticoagulants, antiarrhythmics, digoxin, nitrates and vasoactive drugs, devices, revascularization, and surgical procedures (22,23). No specific algorithm for drug therapy introduction or intensification was used. The need for additional outpatient visits and intravenous diuretic administration were left to the discretion of the clinician in charge of the patient.
The CA125 strategy followed a pre-specified algorithm (Online File 2) aimed at keeping CA125 levels at 35 U/ml or less by means of diuretic dose optimization, enforcing the use of statins, and increasing the frequency of monitoring visits.
The primary endpoint was the composite of 1-year all-cause mortality or readmission for AHF. Readmission for AHF was defined as any unplanned hospitalization requiring a stay >24 h, and caused by substantive worsening of HF requiring intravenous administration of diuretics, inotropes, or vasodilators. Secondary endpoints included: 1) the composite of 1-year death or readmission for any cause; 2) all-cause mortality and days alive out of hospital; 3) recurrent hospitalizations; 4) episodes of worsening HF not requiring hospitalization; and 5) depiction of CA125 and natriuretic peptides’ trajectories over follow-up. Specific definitions of endpoints are described elsewhere (21).
Safety endpoints included the evaluation and comparison of incidence rates of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 min/ml/m2), hypertransaminasemia, hyperkalemia, hypokalemia, and elevated total creatine kinase.
On the basis of prior observations, we expected that the CA125 strategy would translate into 35% relative risk reduction of the primary endpoint. Thus, using an 80% power to detect at least such difference at 1 year, and using a 1:1 allocation ratio, 180 patients were estimated on each group (n = 360) (21). The total sample was increased to 380 patients to account for ineligibility criteria and loss to follow-up, which was assumed to be around 5% (21).
All statistical comparisons were made under the intention-to-treat principle. Results are presented as frequencies, mean ± SD, or median (interquartile range [IQR]), as appropriate. Between-group comparisons were performed using t test, Mann-Whitney test, or Fisher exact test. Differences in count among strategies are presented as incidence rate ratio (IRR).
Patient follow-up was censored at the time of death, new diagnosis of cancer, cardiac valve surgery, or transcatheter intervention. Differences between treatment groups were depicted with the Kaplan-Meier method and tested by the Peto-Peto test. The proportional hazards assumption was checked for the type of strategy against each endpoint using Schoenfeld residuals. When the proportionality assumption was untenable, a restricted mean survival time (RMST) difference was used as a global measure of treatment efficacy (24). A Cox proportional hazards model stratified by center was used to estimate hazard ratio (HR). Pre-specified subgroup analyses included >75 years of age, gender, ischemic etiology, left ventricular ejection fraction (LVEF) >50%, CA125 above median, natriuretic peptides above median, and eGFR <60 ml/min/1.73 m2.
The cumulative rate of readmissions (AHF and all cause) were plotted against time and compared by the Ghosh and Lin estimator (25), which accounts for death as a terminal event. The longitudinal counterpart of the primary endpoint included all episodes of AHF rehospitalization as recurrent events. One simple strategy for incorporating death into analyses of this endpoint is to consider this outcome as an additional event in the recurrent event process (26). That is, one considers a composite of recurrent AHF hospitalizations and death. This updated recurrent event process was analyzed using multilevel negative binomial regression for longitudinal data. A secondary longitudinal endpoint included all episodes of all-cause rehospitalization, with death accounted in a similar way. The difference between strategies from both longitudinal endpoints is expressed as IRR.
CA125 and natriuretic peptides’ longitudinal trajectories
Measured values of CA125 and natriuretic peptides at pre-planned visits were plotted against time and their trajectory difference among strategies tested by means of joint modeling of longitudinal and survival data (27). A short description about this method is presented in Online File 3. Missing values of NT-proBNP (n = 61) were imputed using BNP and other covariates within a multiple imputation framework (chained equations imputation).
This analysis aimed to evaluate the role of NT-proBNP changes on the primary endpoint, and how this marker influences the endpoint–treatment strategy association. Only those values of NT-proBNP that precede the occurrence of the endpoint were included. Two joint models were built: Model 1 included logNT-proBNP and treatment strategy as main effects and Model 2 included the interaction between logNT-proBNP and the treatment strategy.
A 2-sided p value of <0.05 was considered to be statistically significant for all analyses. All analyses were performed using Stata 14.1 (StataCorp LP, College Station, Texas) and R package (R Development Core Team, Vienna, Austria).
Of 380 patients included in this study, 187 were randomly assigned to the CA125 strategy and 193 to were assigned to SOC (Figure 1). Randomization took place at discharge from the index admission in 97.9% (n = 372), with the rest within the first week after discharge.
The mean age of the study population was 73.7 ± 11.1 years, 44.2% were women, and 40.3% exhibited LVEF >50%. Baseline characteristics across treatment arms are shown in Table 1. Overall, there were no differences between both treatment strategies with the exception of higher proportion of hypertension and diabetes mellitus in the CA125-guided arm.
According to the protocol, patients were evaluated at randomization (visit 0, n = 380), 30 days (visit 1, n = 363), 6 months (visit 2, n = 334), and 1 year (visit 3, n = 298). The median time since randomization was 26 days (IQR: 23 to 33 days), 183 days (IQR: 175 to 196 days), and 363 days (IQR: 352 to 371 days) to visit 1, visit 2, and visit 3, respectively.
During the course of the trial, the group allocated to the CA125 strategy had more visits (pre-specified and optional) compared with those allocated to SOC (5.97 visits/person-year vs. 5.23 visits/person-year, respectively; IRR: 1.14; p = 0.003).
Beta-blockers, ACEI or ARB, and aldosterone receptor blockers
There was no difference in prescription frequencies for beta-blockers, ACEI or ARB, and aldosterone receptor blockers either at randomization or at the end of the study. For aldosterone receptor blockers, doses were more frequently up-titrated among the CA125-guided patients (Table 2).
Oral loop diuretics
There were no differences in the frequency or dose of loop diuretics, either at randomization or at the end of the study (Table 2). However, the CA125-guided strategy was associated with higher frequency of furosemide equivalent dose (FED) adjustments (up- or down-titration) as compared with SOC (Table 2). Figure 2 depicts the trajectory of FED stratified by treatment strategy and the simultaneous status of CA125. FED values were consistently higher when CA125 was >35 U/ml in all patients (110 ± 71 vs. 80 ± 55; p < 0.001). Indeed, FED longitudinal profile was close to 20 mg/day higher in patients with CA125 >35 U/ml (p = 0.038). In those with CA125 ≤35 U/ml, FED was not different between the 2 strategies (Figure 2).
Ambulatory intravenous furosemide
The percentage of patients and rates at which intravenous furosemide was administered in HF ambulatory units was higher for the CA125-guided strategy (21.0% vs. 11.0%; p = 0.008; 0.58 administrations/person-year vs. 0.28 administrations/person-year; IRR: 2.11; p < 0.001). Specifically, 19 (10.2%) patients in the CA125-guided arm had 2 or more sessions of intravenous furosemide compared with 11 (5.7%) of those assigned to SOC (p = 0.019) (Figure 2).
Frequency of thiazide prescriptions at randomization and at the end of the study was similar among strategies; nevertheless, there was a trend toward a higher number of dose adjustments (and dose increase) in the active arm (Table 2).
Statin therapy was more frequently prescribed in the CA125-guided group at randomization (82.4% vs. 53.4%; p < 0.001) and at the end of the trial (78.1% vs. 41.5%; p < 0.001). The rate at which statin doses changed did not differ between the 2 arms. However, a decrease in statin doses was more frequently observed in the SOC arm (Table 2).
No significant differences were found for the proportion of patients treated with ivabradine and digoxin either at randomization or at the end of trial (Table 2). Likewise, no differences regarding revascularization procedures (3.9% vs. 4.2%; p=1.00), cardiac valve replacement (0.6% vs. 0.5%; p=1.00), implantable cardioverter-defibrillator implant (2.8% vs. 6.3%; p = 0.137), cardiac resynchronization therapy (1.7% vs. 1.1%; p = 0.678), or ultrafiltration techniques (4.4% vs. 2.2%; p = 0.405) were found across both strategies. The percentage of patients at which intravenous iron was administered was higher for the CA125-guided strategy (Table 2).
Outcomes evaluated as time to first event
The CA125 strategy resulted in a reduction of the proportion of events (66 [35.3%] vs. 84 [43.5%]; p = 0.101). Kaplan-Meier plot showed the 2 curves widely separated over the follow-up, but with differences that decreased over time (Figure 3A). For this endpoint, the variable type of strategy did not follow the proportionality assumption (Schoenfeld residuals p = 0.018), not allowing us to measure its effect with a single HR. Instead, we estimated HRs using Cox regression at 3 months (HR: 0.48; 95% confidence interval [CI]: 0.30 to 0.75; p = 0.002), 6 months (HR: 0.64; 95% CI: 0.43 to 0.95; p = 0.028), 9 months (HR: 0.71; 95% CI: 0.50 to 1.01; p = 0.058), and 12 months (HR: 0.72; 95% CI: 0.52 to 0.99; p = 0.049). More importantly, however, was that the difference in RMST between the 2 strategies was significant (0.08 years; 95% CI: 0.02 to 0.15 years; p = 0.017) in favor of the CA125 strategy (0.74 years vs. 0.66 years). Expressed in days, this means that patients in the CA125 strategy had, on average, 30 days more time free of event in a 1-year framework.
We found no interactions between treatment strategies and any of the pre-specified subgroups (Online File 4).
Composite of death or any rehospitalization
The number of events in the CA125 strategy versus SOC was 84 (44.9%) versus 97 (50.3%), respectively (p = 0.297). The difference in RMST between the 2 strategies was used as the main approach for efficacy measure, on the basis that the proportionality assumption was untenable (Schoenfeld residuals p = 0.050). The RMST for the CA125 strategy and SOC was 0.67 years versus 0.61 years, respectively, with a difference of 0.054 years (95% CI: –0.018 to 0.125 years; p = 0.142) (Figure 3B).
All-cause mortality and days alive and out of the hospital
There were no differences in the proportion of events between the 2 strategies (31 [16.6%] vs. 35 [18.1%]; p = 0.689). The HR as a measure of global effect was not significant (HR: 0.92; 95% CI: 0.57 to 1.49; p = 0.735) (Online File 5A). Likewise, no differences were found for mortality rates using days alive and out of the hospital (Peto-Peto test: p = 0.732) (Online File 5B).
Recurrent hospitalizations including outside hospital death as additional readmission
The CA125 strategy showed a significant reduction in the rate of recurrent AHF (as a part of the primary endpoint) and all-cause rehospitalization: 85 events versus 165 events (IRR: 0.49; 95% CI: 0.28 to 0.82; p = 0.008) and 132 events versus 202 events (IRR: 0.61; 95% CI: 0.39 to 0.96; p = 0.033), respectively. Figures 3C and 3D show the mean number of recurrences for AHF and all-cause hospitalization, respectively.
Recurrent hospitalizations (no adjustment for death as terminal event)
There was a superiority of the CA125 strategy in reducing rates for recurrent AHF hospitalizations (0.40 events/person-year vs. 0.85 events/person-year; IRR: 0.47; 95% CI: 0.35 to 0.63; p < 0.001) and all-cause hospitalizations (0.67 events/person-year vs. 1.06 events/person-year; IRR: 0.63; 95% CI: 0.50 to 0.80; p < 0.001).
Emergency room visits for AHF not requiring hospitalization
Patients in the CA125-guided arm had fewer visits to the emergency department (with duration <24 h) as compared with the SOC group (10.7% vs. 17.1%; p = 0.077). This difference becomes significant when expressed as events per person-year (0.16 events/person-year vs. 0.28 events/person-year; p = 0.008).
CA125 and NT-proBNP trajectories
CA125 values decreased over time in both treatment arms, especially between randomization and visit 1. Lower mean values were found in CA125 strategy, particularly after the third month (p = 0.027) (Online File 6). LogNT-proBNP decreased over time in both arms without significant differences at randomization and 30 days. At 6 months and 1 year logNT-proBNP was lower in SOC (Online File 7).
NT-proBNP changes and the primary endpoint
The strategy guided by CA125 reduced the incidence of the composite endpoint by 38% on average, despite adjustment by longitudinal values of logNT-proBNP (HR: 0.62; 95% CI: 0.44 to 0.86; p = 0.005). In addition, the predictive effect of logNT-proBNP was uniformly present between the 2 arms with no difference among them (p value for interaction = 0.924).
Rates of eGFR <60 ml/min/1.73 m2 were higher in the CA125-guided arm (IRR: 1.25; 95% CI: 1.07 to 1.47; p = 0.004); however, this difference did not translate into an increase in the rate for acute renal failure hospitalizations (3.1% vs. 1.5%; p = 0.335). In addition, we found no differences in the frequency of hospitalizations due to hyperkalemia (0.53% vs. 0%; p = 0.493), hypokalemia (1.06% vs. 0.52%; p = 0.619), or any other safety endpoint for the SOC and CA125-guided arms, respectively.
Despite the associated high risk of adverse outcomes, the evidence about the optimal therapeutic approach after discharge from AHF is largely unknown (1–3). To explore new avenues about the optimal management of these patients, we designed a randomized controlled trial to compare the effect of a CA125-guided strategy versus SOC on the composite of 1-year death or readmission for AHF. At its face value, this strategy was characterized by an increase in the frequency of patients’ monitoring, optimization of the use of diuretics, and increase in the use of statins. Under this strategy, there was a significant reduction in the primary endpoint, the cumulative risk of readmissions (HF-related [∼50%] as well as all-cause readmission [∼40%]), and visits to emergency room (∼40%). Interestingly, this effect was homogeneous among all pre-specified subgroups and independent of changes in natriuretic peptides. Participants were selected by the levels of CA125. By using this scheme, a significant proportion of high-risk patients (elderly subjects, women, and patients with preserved ejection fraction) were well represented in this trial.
In contrast to other biomarker-guided trials in which management strategies are on the basis of evidence-based therapies (5,6), our CA125-guided approach focused on empirical, and sometimes controversial, interventions.
By exploiting the assumption about the surrogacy of CA125 for fluid overload, the dose titration of loop-diuretic treatment was an important component of the active strategy. Indeed, in the CA125 strategy, the FED titration (either up or down) was about 50% more frequent as compared with the control arm. Additionally, up to 21% of these patients received ambulatory administration of intravenous furosemide on the basis of clinical profile and CA125 response. Furthermore, ARB were more frequently up-titrated. Perhaps the limited sensitivity and specificity of symptoms or signs for the clinical assessment of fluid overload (9,10) have contributed to the inertia in the use of loop diuretics in this setting.
Even though contemporary guidelines do not endorse a routine use of statins in HF (23,24), some observational data have suggested a beneficial effect by reducing readmission rates in patients with HF and elevated inflammatory activity (28). Fueled by the observed correlation between CA125 and inflammation markers in HF (13), we decided to add statins as a component of the CA125 strategy. In the end, 80% of patients in the active arm received statins without relevant safety issues. Probably as a consequence of patient’s close monitoring, the frequency of intravenous iron administration was higher in the CA125 strategy.
On the contrary, there were no differences on the use of beta-blockers, ACEI or ARB, and other pharmacological and nonpharmacological treatments between the 2 strategies. Worth noticing is that the use of these evidence-based therapies met the standard recommended by the guidelines.
Logistic aspects about this biomarker, such as its wide availability, standardized measurement, and low cost, offer additional advantages for its fast implementation in the routine management of HF. In addition, plasma CA125 appears not significantly influenced by gender, LVEF, and renal function. Interestingly, the half-life reported for this biomarker (around 5 to 12 days) (13) could provide useful clinical and pathophysiological information of the prior weeks, in a similar fashion as glycated hemoglobin in diabetes.
This trial is not exempt of limitations. First, not including patients with a low-normal CA125 limits the external validity of our findings. We believe that including these patients would have made it easier to detect a significant difference between the 2 management strategies, and would have reinforced the role of this biomarker for guiding therapy. Nonetheless, the inclusion of these patients in a larger trial deserves further consideration in the future. Second, not having the randomly assigned strategy being blinded from the physician and nurses in charge of the patient is indeed a potential threat to the internal validity of the trial. However, the information about patients’ levels of CA125 is mandatory for treatment monitoring. Third, this is a strategy comparison (holistic approach), and thus it is not possible to isolate the effect of individual components that make up the active strategy. Fourth, in some cases, the trajectory of CA125 could have been influenced by other nondiagnosed subclinical conditions different from HF. Fifth, the fact that most of the effect of the guided strategy involved the readmission component of the endpoints suggests that we may need a bigger sample size and longer trial duration to detect a significant effect on mortality. Sixth, due to limited sample size, we cannot rule out false negative results due to type II error when testing the interactions in the subgroup analyses. Last, the lack of effect on days alive and out of the hospital, despite the significant reduction on readmissions, suggests that the avoided hospitalizations in the active arm were in those with lower severity and hence shorter stays.
After being discharged for AHF, a CA125-guided therapy aiming to keep CA125 levels below 35 U/ml was associated with a reduced risk of 1-year adverse outcomes. This effect was mainly driven by significantly reducing the rate of rehospitalizations.
COMPETENCY IN MEDICAL KNOWLEDGE: Morbimortality following an episode of AHF remains high. Unfortunately, the optimal therapeutic approach in this setting is not well defined, especially regarding the intensity of depletive therapies, use of statins, and frequency of monitoring. CA125 has shown to be a reliable prognostic marker, and a proxy of fluid overload and inflammatory activity. The fact that plasma levels of this marker respond to the intensity of diuretic use opens the potential use of this biomarker as a guiding therapy tool. The results of this trial supported the superiority of a CA125-guided strategy (as compared with SOC), in terms of reducing the risk of the composite of 1-year death or AHF readmission. Building on the hope that our results will be reproduced in further trials, a CA125-guided strategy will pave the road toward a more accurate management of patients with AHF.
TRANSLATIONAL OUTLOOK: Larger studies are needed to confirm our results and define the real clinical impact of the CA125-guided therapy after an episode of AHF.
The authors thank the study coordinators, nurses, and staff at the investigative sites and especially all of the patients involved in this trial. Special acknowledgment to Marta Peiró (INCLIVA), Gemma Romero (INCLIVA), Anna Mollar (INCLIVA), Estefania Montalvo (INCLIVA), Amparo Villaescusa (INCLIVA), and INCLIVA workers for the logistic and institutional support. These individuals received no compensation for their contributions.
For a complete list of the CHANCE-HF investigators and an expanded Methods section as well as supplemental figures and a table, please see the online version of this article.
This study was funded with public funds obtained in competitive calls: grant EC10-108 of the Ministry of Health Call for Independent Clinical Research in year 2010. The authors also received the support of CAIBER (CAI11/01/0039), SCReN-Spanish Clinical Research Network (PT13/0002/0031) from the National R+D+I Plan of the Institute of Health Carlos III (Ministry of Economy and Competitiveness: Co-financed by European Regional Development Fund “A way to make Europe”), Red de Investigación Cardiovascular, Programa 7 (RD12/0042/0010 and RD/12/0042/0068) FEDER, and PIE15/00013. Dr. Núñez received support to organize a CHANCE-HF researcher meeting at 2012 and 2013 by Servier and Ferrer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- angiotensin-converting enzyme inhibitors
- acute heart failure
- angiotensin II receptor antagonists
- B-type natriuretic peptide
- carbohydrate antigen-125
- confidence interval
- furosemide equivalent dose
- hazard ratio
- heart failure
- incidence rate ratio
- N-terminal pro–B-type natriuretic peptide
- standard of care
- Received March 1, 2016.
- Revision received June 23, 2016.
- Accepted June 23, 2016.
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