Abstract
OBJECTIVE:
We aimed to evaluate angiotensin receptor blocker add-on therapy in patients with low cardiac output during decompensated heart failure.
METHODS:
We selected patients with decompensated heart failure, low cardiac output, dobutamine dependence, and an ejection fraction <0.45 who were receiving an angiotensin-converting enzyme inhibitor. The patients were randomized to losartan or placebo and underwent invasive hemodynamic and B-type natriuretic peptide measurements at baseline and on the seventh day after intervention. ClinicalTrials.gov: NCT01857999.
RESULTS:
We studied 10 patients in the losartan group and 11 patients in the placebo group. The patient characteristics were as follows: age 52.7 years, ejection fraction 21.3%, dobutamine infusion 8.5 mcg/kg.min, indexed systemic vascular resistance 1918.0 dynes.sec/cm5.m2, cardiac index 2.8 L/min.m2, and B-type natriuretic peptide 1,403 pg/mL. After 7 days of intervention, there was a 37.4% reduction in the B-type natriuretic peptide levels in the losartan group compared with an 11.9% increase in the placebo group (mean difference, -49.1%; 95% confidence interval: -88.1 to -9.8%, p = 0.018). No significant difference was observed in the hemodynamic measurements.
CONCLUSION:
Short-term add-on therapy with losartan reduced B-type natriuretic peptide levels in patients hospitalized for decompensated severe heart failure and low cardiac output with inotrope dependence.
Renin-Aldosterone System; Hemodynamic; Low Cardiac Output; Vasodilation; Natriuretic Peptide
INTRODUCTION
The management approach for stable chronic heart failure has been established by guidelines (11. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, et al. 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. Circulation. 2009;119(14):1977-2016.) that were developed using data from randomized clinical trials. However, during heart failure, decompensation-specific interventions have not been well studied. Moreover, heart failure patients require hospitalization, and sometimes they are in critical condition, presenting problems such as a low cardiac output. In this context, fewer clinical trials have been performed.
The intravenous administration of inotropes may be necessary for heart failure
patients with low cardiac output if intravenous vasodilator therapy is not possible
(22. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M,
Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and
chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of
Acute and Chronic Heart Failure 2012 of the European Society of Cardiology.
Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
Eur J Heart Fail. 2012;14(8):803-69.). In end-stage heart failure, patients
frequently become dependent on inotrope, which predicts greater mortality (33. Ochiai ME, Cardoso JN, Vieira KR, Lima MV, Brancalhao EC,
Barretto AC. Predictors of low cardiac output in decompensated severe heart
failure. Clinics. 2011;66(2):239-44,
http://dx.doi.org/10.1590/S1807-59322011000200010.
http://dx.doi.org/10.1590/S1807-59322011...
). Generally, these patients die if they
cannot receive a heart transplant, either because of clinical conditions or because
of the lack of available donor organs. Therefore, it is important to find
alternative options so that inotropes can be withdrawn as soon as possible.
During decompensated heart failure, activation of the renin-angiotensin-aldosterone
system persists, with increases in plasma renin activity and serum levels of
angiotensin II and aldosterone, despite the use of angiotensin-converting enzyme
(ACE) inhibitors (44. Johnson W, Omland T, Hall C, Lucas C, Myking OL, Collins C, et
al. Neurohormonal activation rapidly decreases after intravenous therapy with
diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol.
2002;39(10):1623-9,
http://dx.doi.org/10.1016/S0735-1097(02)01814-4.
http://dx.doi.org/10.1016/S0735-1097(02)...
). In advanced heart
failure patients, a state of low cardiac output could be present during a
decompensated period; consequently, the use of ACE inhibitors might not be adequate
for controlling vasoconstriction (55. Mullens W, Abrahams Z, Francis GS, Sokos G, Starling RC, Young
JB, et al. Usefulness of isosorbide dinitrate and hydralazine as add-on therapy
in patients discharged for advanced decompensated heart failure.
Am J Cardiol. 2009;103(8):1113-9,
http://dx.doi.org/10.1016/j.amjcard.2008.12.028.
http://dx.doi.org/10.1016/j.amjcard.2008...
).
Although many clinical trials have been performed to examine drug therapies for
stable chronic heart failure, clinical trials are lacking for drug therapy during
decompensated heart failure, mainly with inotrope dependence (66. Felker GM, Pang PS, Adams KF, Cleland JG, Cotter G, Dickstein K,
et al. Clinical trials of pharmacological therapies in acute heart failure
syndromes: lessons learned and directions forward. Circ Heart Fail.
2010;3(2):314-25,
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.893222.
http://dx.doi.org/10.1161/CIRCHEARTFAILU...
). In this context, short-term outcomes should have priority
(77. Gheorghiade M, De Luca L, Fonarow GC, Filippatos G, Metra M,
Francis GS. Pathophysiologic targets in the early phase of acute heart failure
syndromes. Am J Cardiol. 2005;96(6A):11G-17G,
http://dx.doi.org/10.1016/j.amjcard.2005.07.016.
http://dx.doi.org/10.1016/j.amjcard.2005...
).
The dual blockade of the renin-angiotensin-aldosterone system with an ACE inhibitor
and an AT1 angiotensin receptor blocker (ARB) used together has been demonstrated to
be beneficial in heart failure patients (88. McMurray JJ, Östergren J, Swedberg K, Granger CB, Held P,
Michelson EL, et al. Effects of candesartan in patients with chronic heart
failure and reduced left-ventricular systolic function taking
angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet.
2003;362(9386):767-71,
http://dx.doi.org/10.1016/S0140-6736(03)14283-3.
http://dx.doi.org/10.1016/S0140-6736(03)...
,99. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial
Investigators. A randomized trial of the angiotensin-receptor blocker valsartan
in chronic heart failure. N Engl J Med.
2001;345(23):1667-75.). However, this dual
inhibition has not been studied during heart failure decompensation or even when low
cardiac output is present.
The objective of this study was to assess the effects of add-on therapy with angiotensin receptor blocker on plasma B-type natriuretic peptide (BNP) levels and hemodynamic measurements in heart failure patients with low cardiac output during hospitalization for decompensation.
METHODS
This study was carried out in the heart failure compensation unit of a tertiary
cardiology center at a university hospital. Patients who are typically hospitalized
in our medical facility are those with severe advanced heart failure in a
decompensation period that does not respond to initial therapy; frequently, these
patients present with low cardiac output (1010. Cardoso J, Novaes M, Ochiai M, Regina K, Morgado P, Munhoz R, et
al. Chagas cardiomyopathy: prognosis in clinical and hemodynamic profile C. Arq
Bras Cardiol. 2010;95(4):518-23,
http://dx.doi.org/10.1590/S0066-782X2010005000112.
http://dx.doi.org/10.1590/S0066-782X2010...
). In our service, dobutamine is preferred over milrinone. It is not
uncommon for some patients to experience dobutamine dependence and not be able to
tolerate inotropic withdrawal.
Patients
This was a randomized, double-blind, placebo-controlled clinical trial. The
inclusion criteria were as follows: hospitalization for decompensated heart
failure, defined by worsening of symptoms until fatigue or dyspnea at rest; low
cardiac output, defined by the clinical-hemodynamic profile (44. Johnson W, Omland T, Hall C, Lucas C, Myking OL, Collins C, et
al. Neurohormonal activation rapidly decreases after intravenous therapy with
diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol.
2002;39(10):1623-9,
http://dx.doi.org/10.1016/S0735-1097(02)01814-4.
http://dx.doi.org/10.1016/S0735-1097(02)...
); dobutamine dependence; ejection
fraction <0.45; spontaneous breathing; and receiving ACE inhibitors. The
patients could have jugular ingurgitation, lower limb edema, ascites, and rales.
Dobutamine dependence was defined by infusion for more than 15 days or an
unsuccessful attempt at withdrawal. The exclusion criteria were as follows:
serum creatinine >3.0 mg/dL, serum K>6.0 mEq/L, systolic blood
pressure <70 mm Hg, aortic stenosis, and acute coronary syndrome in the
previous 2 months. The patients were then assigned by permuted block
randomization to 4 groups, stratified by sex, to losartan or placebo. The
endpoints were changes in the BNP levels, cardiac index, pulmonary wedge
capillary pressure, systemic vascular resistance, and successful withdrawal of
dobutamine.
With a power of 80% and an estimated 45% reduction in BNP level between losartan and placebo, the calculated sample size was 18 patients. As a secondary endpoint, we estimated rates of successful withdrawal of 17% and 68% for patients in the placebo group and the ARB group, respectively, on the basis of our previous study (1111. Ochiai ME, Barretto AC, Cardoso JN, Munhoz RT, Morgado PC, Ramires JA. Angiotensin II receptor blocker add-on therapy for low cardiac output in decompensated heart failure. Arq Bras Cardiol. 2010;94(2):219-22.).
Intervention procedures
Patients were allocated to the losartan or placebo group. Losartan or placebo was administered at 25 mg bid and increased to 50 mg bid 3 days later. The procedures were performed in a double-blind fashion for the first 7 days to control hemodynamic effects and for at least 3 more days until the attempt at dobutamine withdrawal. Captopril was the standardized ACE inhibitor used and was maintained unchanged during the double-blind period.
Hemodynamic monitoring
The patients underwent pulmonary artery catheterization, and cardiac output was obtained using the thermodilution technique (1212. Voyce SJ, Urbach D, Rippe JM. Pulmonary artery catheters. In: Rippe JM, Irwin RS, Alpert JS, Fink MP (eds). Intensive Care Medicine 2nd ed. Little, Boston: Brown and Company; 1991. p. 48-72.). The hemodynamic data obtained included cardiac index, pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrium pressure. Indexed systemic vascular resistance and indexed pulmonary vascular resistance were calculated. Hemodynamic measurements were performed at baseline and 7 days after the start of the intervention. The patients retained a percutaneous sheath introducer, and pulmonary artery catheters were used only for these two measurements.
BNP levels were measured using the automated immunoassay method at baseline and 7 days later. BNP serum levels were transformed by logarithmic correction. Subsequently, the changes incurred in the losartan and placebo groups were assessed by repeated-measures ANOVA.
Adverse events
Adverse events included the occurrence of hypotension (systolic blood pressure below 70 mm Hg), hyperkalemia (K above 6.0 mEq/L), and worsening renal function (serum creatinine above 3.0 mg/dL). If the systolic blood pressure dropped below 70 mmHg, the daily dose of losartan or placebo was reduced by half. If this hypotension persisted, losartan or placebo was suspended.
Statistical analysis
The analysis was performed on an intention-to-treat basis and included all
randomized patients. Continuous variables are expressed as the mean and standard
deviation and were compared between the ARB and control groups by Student's
t test. Categorical variables are expressed as numbers and proportions and were
compared using the chi-square test or Fisher's test. Continuous variables
at baseline and after the intervention were analyzed between groups using
repeated measures ANOVA (1313. Diggle PJ. An approach to the analysis of repeated measurements.
Biometrics. 1988;44(4):959-71,
http://dx.doi.org/10.2307/2531727.
http://dx.doi.org/10.2307/2531727...
).
P-values<0.05 (2-tailed) were considered
significant.
Clinical interest variables or variables with p<0.100 by
bivariate analysis underwent multivariate analysis by logistic regression (1414. Hosmer DW, Lemeshow S. Applied Logistic Regression. New York:
Wiley. 1989.) to calculate the odds ratios and
respective 95% confidence intervals. Event free survival curves were constructed
using the Kaplan-Meier method (1515. Kaplan EL, Meier P. Nonparametric estimation from incomplete
observations. J Am Stat Assoc. 1958;53:457-81,
http://dx.doi.org/10.1080/01621459.1958.10501452.
http://dx.doi.org/10.1080/01621459.1958....
) and
compared using the log-rank test (1616. Cox DR, Oakes D. Analysis of Survival Data. 1st ed. London:
Chapman and Hall. 1984.).
The mortality predictors were identified by Cox regression (1717. Cox DR. Regression Models and Life-tables. J Royal
Statistical Society. 1972;34(2):187-220.).
This study was approved by the research ethics committee of our institution and is registered with the Brazilian Health Ministry and with the Clinical Trials (www.clinicaltrials.gov; NCT 01857999). The patients or their guardians read and signed the informed consent form. This study was conducted according the principles of the Helsinki Declaration (2004).
RESULTS
We selected 21 patients between August 2008 and December 2010. The characteristics of the included patients were as follows: age 52.7 (SD = 11.5) years, ejection fraction 21.3% (SD = 5.8), dobutamine infusion 8.5 (SD = 3.8) mcg/kg.min, systolic blood pressure 98.5 (SD = 12.2) mmHg, pulmonary wedge capillary pressure 30.7 (SD = 7.7) mmHg, indexed systemic vascular resistance 1,918 (SD = 556) dynes.sec.cm-5.m-2, systemic vascular resistance 1,132 (SD = 371) dynes.sec.cm-5, cardiac index 2.8 (SD = 0.7) L/min.m2, and BNP 1,403 (SD = 950) pg/mL. There were 10 (47.6%) patients with Chagas disease. See Table 1 for the complete baseline characteristics.
After 7 days, the BNP levels decreased (Figure 1) by 37.4% in the losartan group and increased by 11.9% in the placebo group (mean difference -49.1%; 95% CI: -88.1 to -9.8%, p = 0.018).
There was no significant difference in the hemodynamic measurements. The systolic blood pressure decreased by 5.9% in the losartan group and by 3.2% in the placebo group (p = 0.796). The indexed systemic vascular resistance decreased by 7.7% in the losartan group vs. 10.5% in the placebo group (p = 0.280). The cardiac index increased by 6.7% and 6.9% in losartan and placebo groups, respectively (p = 0.203). The pulmonary capillary wedge pressure decreased by 22.9% and 5.1% in the losartan and placebo groups, respectively (p = 0.459). There were no complications related to the pulmonary artery catheter.
Successful dobutamine withdrawal occurred in 4/10 (40%) patients in the losartan group vs. 3/11 (27.3%) patients in the placebo group (p = 0.537 by logistic regression). The odds ratio was 1.78 (95% CI: 0.20 to 16.4) for successful dobutamine withdrawal in the losartan group.
The occurrence of adverse events was similar in both groups. A drop in systolic blood pressure below 70 mm Hg occurred in 3 (30%) patients in the losartan group and in 1 (9.1%) patient in the placebo group (p = 0.223); however, no persistent hypotension occurred. None of the patients in either group had hyperkalemia. Two patients (one patient from each group) had an increase in serum creatinine (>0.3 mg/dL) (p = 0.943). See Table 2 for changes in the laboratory measurements.
After a follow-up of 465 days (95% CI: 317 to 613), 10 patients died (5 in each group) (p = 0.640), as shown in Figure 2. Cox regression identified heart failure with ischemic etiology as an independent predictor of all-cause mortality, with a relative risk of 14.3 (95% confidence interval: 1.6 to 130.0, p = 0.019).
DISCUSSION
The main finding of this study was the decline in BNP levels with angiotensin-receptor blocker add-on therapy in patients with acute decompensated heart failure and a low cardiac output state. Systemic vascular resistance, cardiac index, and pulmonary wedge capillary pressure remained unchanged, as did the clinical endpoint. These findings are based on 42 hemodynamic and BNP measurements in 21 patients.
The novelty of the present study lies in the demonstration of a more intense
reduction in BNP levels (37.4%) with add-on ARB therapy during decompensation
(compared with 25% in stable outpatients). Moreover, this effect was achieved in a
7-day period, whereas a 22-week period was reported in a previous study (1818. Mitrovic V, Appel KF, Proskynitopoulos N, Dereli S, Hamm CW.
Effects of candesartan cilexetil “add-on” treatment in congestive
heart failure outpatients in daily practice. Clin Res Cardiol.
2009;98(6):379-89, http://dx.doi.org/10.1007/s00392-009-0011-7.
http://dx.doi.org/10.1007/s00392-009-001...
). In another study with stable class II-III
heart failure patients, candesartan add-on therapy reduced amino-terminal proBNP by
20% in 6 months (1919. White M, Lepage S, Lavoie J, De Denus S, Leblanc MH, Gossard D,
et al. Effects of combined candesartan and ACE inhibitors on BNP, markers of
inflammation and oxidative stress, and glucose regulation in patients with
symptomatic heart failure. J Card Fail. 2007;13(2):86-94,
http://dx.doi.org/10.1016/j.cardfail.2006.10.013.
http://dx.doi.org/10.1016/j.cardfail.200...
). Different from stable
heart failure patients, the management of patients with decompensation requires
specific strategies. For this reason, add-on ARB therapy could be more important
during heart failure decompensation, when BNP levels and neuro-hormonal activation
are higher (44. Johnson W, Omland T, Hall C, Lucas C, Myking OL, Collins C, et
al. Neurohormonal activation rapidly decreases after intravenous therapy with
diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol.
2002;39(10):1623-9,
http://dx.doi.org/10.1016/S0735-1097(02)01814-4.
http://dx.doi.org/10.1016/S0735-1097(02)...
).
A generally low cardiac output state during decompensation of heart failure is often
neglected in randomized clinical trials. Moreover, patients with unsuccessful
withdrawal of inotropic therapy have mortality rates higher than 79% (2020. Caccamo MA, Eckman PM. Pharmacologic therapy for New York Heart
Association class IV heart failure. Congest Heart Fail. 2011;17(5):213-9,
http://dx.doi.org/10.1111/j.1751-7133.2011.00235.x.
http://dx.doi.org/10.1111/j.1751-7133.20...
). Our findings could be particularly
important for inotrope-dependent heart failure patients who are not able to receive
a heart transplant. For these patients, the effects of drug therapy should be faster
and more intensive than for patients with mild disease.
In addition, the lower ejection fraction, the low cardiac output, the higher systemic vascular resistance, and the higher BNP levels demonstrated the severity of heart failure in our patients.
Hemodynamic condition during heart failure decompensation
We found high systemic vascular resistance and high pulmonary capillary wedge
pressure in our patients during acute heart failure decompensation. The high
systemic vascular resistance occurred despite the fact that the patients were
taking a high dose of an ACE inhibitor (captopril: 134 mg/d). In fact, Parker et
al. observed a reduction in systemic vascular resistance in patients with severe
heart failure who were taking ACE inhibitors; however, this resistance remained
above the normal values (2121. Packer M, Lee WH, Medina N, Yushak M, Kessler PD. Functional
renal insufficiency during long-term therapy with captopril and enalapril in
severe chronic heart failure. Ann Intern Med. 1987;106(3):346-54,
http://dx.doi.org/10.7326/0003-4819-106-3-346.
http://dx.doi.org/10.7326/0003-4819-106-...
,2222. Viecili PR, Pamplona D, Park M, Silva SR, Ramires JA, Da Luz PL.
Antagonism of the acute hemodynamic effects of captopril in decompensated
congestive heart failure by aspirin administration. Braz J Med Biol
Res. 2003;36(6):771-80,
http://dx.doi.org/10.1590/S0100-879X2003000600013.
http://dx.doi.org/10.1590/S0100-879X2003...
). The cardiac index was normal; however,
all patients were using intravenous inotrope. Our findings are similar to those
of the Escape trial, which justifies the use of multiple vasodilators with
add-on ARB therapy. Interestingly, hemodynamic improvement in the placebo group
occurred even though all medications remained unchanged. Non-pharmacological
factors could be involved in this finding, such as rest, salt restriction,
physiotherapy, and the “inertial” effect of drug therapy before
the hemodynamic measurements.
Dobutamine is indicated for low cardiac output in severe heart failure based on
International Guidelines; however, a meta-analysis describing concerns regarding
the increase in mortality has been published (2323. Tacon CL, McCaffrey J, Delaney A. Dobutamine for patients with
severe heart failure: a systematic review and meta-analysis of randomised
controlled trials. Intensive Care Med. 2012;38(3):359-67,
http://dx.doi.org/10.1007/s00134-011-2435-6.
http://dx.doi.org/10.1007/s00134-011-243...
). Nevertheless, this meta-analysis included outpatients who
received intermittent therapy. Despite these concerns, in practice, physicians
continue to prescribe dobutamine to 22.3% of patients who are hospitalized for
heart failure (2424. Partovian C, Gleim SR, Mody PS, Li SX, Wang H, Strait KM, et al.
Hospital patterns of use of positive inotropic agents in patients with heart
failure. J Am Coll Cardiol. 2012;60(15):1402-9,
http://dx.doi.org/10.1016/j.jacc.2012.07.011.
http://dx.doi.org/10.1016/j.jacc.2012.07...
,2525. Follath F, Yilmaz MB, Delgado JF, Parissis JT, Porcher R, Gayat
E, et al. Clinical presentation, management and outcomes in the Acute Heart
Failure Global Survey of Standard Treatment (ALARM-HF). Intensive Care Med.
2011;37(4):619-26, http://dx.doi.org/10.1007/s00134-010-2113-0.
http://dx.doi.org/10.1007/s00134-010-211...
). Consequently, our results showed that add-on ARB
therapy is an alternative to this high-risk situation (i.e., low cardiac state
and inotrope dependence).
ARB-ACE inhibitor association pathophysiology
The renin-angiotensin-aldosterone system plays an important role in the
pathophysiology of heart failure. In systolic heart failure, activation of this
system occurs, which worsens cardiac remodeling and hemodynamic conditions,
creating a vicious cycle. The blockade of this system with an ACE inhibitor and
an aldosterone antagonist reduces morbidity and mortality.In addition, the
renin-angiotensin-aldosterone system interacts with the cardiac peptide system.
Plasma BNP levels increase in heart failure due to BNP release by myocytes after
distension. BNP has diagnostic and prognostic values in heart failure (2626. Mentz RJ, Felker GM. Natriuretic peptide-guided therapy for
heart failure. Circ J. 2011;75(9):2031-7.). Used as a guide for heart failure
treatment, BNP reduces death, hospital admission, and decompensation, most
likely through higher doses of diuretics, ACE inhibitors, and spironolactone
(2727. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG,
Richards AM. Treatment of heart failure guided by plasma aminoterminal brain
natriuretic peptide (N-BNP) concentrations. Lancet. 2000;355(9210):1126-30,
http://dx.doi.org/10.1016/S0140-6736(00)02060-2.
http://dx.doi.org/10.1016/S0140-6736(00)...
,2828. Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal
E, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in
heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol.
2007;49(16):1733-9,
http://dx.doi.org/10.1016/j.jacc.2006.10.081.
http://dx.doi.org/10.1016/j.jacc.2006.10...
,2929. Berger R, Moertl D, Peter S, Ahmadi R, Huelsmann M, Yamuti S, et
al. N-terminal pro-B-type natriuretic peptide-guided, intensive patient
management in addition to multidisciplinary care in chronic heart failure a
3-arm, prospective, randomized pilot study. J Am Coll Cardiol.
2010;55(7):645-53,
http://dx.doi.org/10.1016/j.jacc.2009.08.078.
http://dx.doi.org/10.1016/j.jacc.2009.08...
). However, the use of
biomarkers such as BNP as a surrogate endpoint remains controversial.
The ARB-ACE inhibitor association has been proven to be beneficial in reducing
clinical events such as cardiovascular mortality and hospitalization (88. McMurray JJ, Östergren J, Swedberg K, Granger CB, Held P,
Michelson EL, et al. Effects of candesartan in patients with chronic heart
failure and reduced left-ventricular systolic function taking
angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet.
2003;362(9386):767-71,
http://dx.doi.org/10.1016/S0140-6736(03)14283-3.
http://dx.doi.org/10.1016/S0140-6736(03)...
,99. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial
Investigators. A randomized trial of the angiotensin-receptor blocker valsartan
in chronic heart failure. N Engl J Med.
2001;345(23):1667-75.). In our study, we applied the tactic of ARB add-on therapy in
patients with more severe heart failure during decompensation and low cardiac
output, and we found a hormonal benefit. The survival analysis did not identify
a difference between the losartan and placebo groups; however, the procedures
were performed in a double-blind fashion for 7 days, and it is very unlikely
that a short-term intervention could have an influence on late outcomes.
The HEAAL study demonstrated that a high dose of losartan reduces the endpoint
rate compared with a low dose (3030. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M,
Martinez FA, et al. Effects of high-dose versus low-dose losartan on clinical
outcomes in patients with heart failure (HEAAL study): a randomised,
double-blind trial. Lancet. 2009;374(9704):1840-8,
http://dx.doi.org/10.1016/S0140-6736(09)61913-9.
http://dx.doi.org/10.1016/S0140-6736(09)...
). The
occurrence of hyperkalemia was 2.79% in the high-dose group and 1.87% in the
low-dose group (p<0.001); creatinine was also increased in
the high-dose group (7.12%) compared with the low-dose group (4.73%)
(p<0.001).
This association has been demonstrated to be beneficial for patients on
hemodialysis, leading to a significant reduction in mortality and
hospitalization (3131. Cice G, Di Benedetto A, D'Isa S, D'Andrea A, Marcelli
D, Gatti E, et al. Effects of telmisartan added to Angiotensin-converting enzyme
inhibitors on mortality and morbidity in hemodialysis patients with chronic
heart failure a double-blind, placebo-controlled trial. J Am Coll Cardiol.
2010;56(21):1701-8,
http://dx.doi.org/10.1016/j.jacc.2010.03.105.
http://dx.doi.org/10.1016/j.jacc.2010.03...
). Adverse
effects—mainly hypotension—occurred in 16.3% of patients in the
ARB group versus 10.7% of patients in the placebo group.
Safety of the ARB-ACE inhibitor association
Safety is another concern related to the ARB-ACE inhibitor association. In the
present study, the ARB-ACE inhibitor association did not increase the occurrence
of adverse effects in the short-term. Use of this association for treatment of
hypertension did not reduce cardiovascular events; rather, it increased adverse
effects (3232. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et
al. Telmisartan, ramipril, or both in patients at high risk for vascular events.
N Engl J Med. 2008;358(15):1547-59.). On the other hand, in heart
failure patients, this association decreased mortality and hospitalization with
an increase of approximately 5% in adverse effects (88. McMurray JJ, Östergren J, Swedberg K, Granger CB, Held P,
Michelson EL, et al. Effects of candesartan in patients with chronic heart
failure and reduced left-ventricular systolic function taking
angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet.
2003;362(9386):767-71,
http://dx.doi.org/10.1016/S0140-6736(03)14283-3.
http://dx.doi.org/10.1016/S0140-6736(03)...
,99. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial
Investigators. A randomized trial of the angiotensin-receptor blocker valsartan
in chronic heart failure. N Engl J Med.
2001;345(23):1667-75.). In addition, a
meta-analysis (3333. Lakhdar R, Al-Mallah MH, Lanfear DE. Safety and tolerability of
angiotensin-converting enzyme inhibitor versus the combination of
angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in
patients with left ventricular dysfunction: a systematic review and
meta-analysis of randomized controlled trials. J Card Fail.
2008;14(3):181-8,
http://dx.doi.org/10.1016/j.cardfail.2007.11.008.
http://dx.doi.org/10.1016/j.cardfail.200...
) revealed a 2.3%
increase in the risk of developing an adverse event. However, patients with more
advanced heart failure are the minority in these studies. The occurrence of
adverse events could be more frequent in patients with more severe disease,
although the benefit could be greater. Moreover, worsening renal function has
special importance because it has been related to a worse prognosis in severe
heart failure (3434. Ochiai ME, Barretto AC, Oliveira MT Jr, Munhoz RT, Morgado PC,
Ramires JA. Uric acid renal excretion and renal insufficiency in decompensated
severe heart failure. Eur J Heart Fail.
2005;7(4):468-74.).
Study limitations
The sample size of our study was small; thus, the analysis of clinical events was somewhat challenging. Our primary endpoint was a change in BNP, which is a surrogate endpoint for clinical events. It is possible that the high percentage of Chagas disease cardiomyopathy interfered with our results because these patients have attenuated vasoconstriction; consequently, multiple vasodilation strategies were not as effective as we expected.
In summary, short-term add-on therapy with losartan reduced BNP levels in patients hospitalized for decompensated severe heart failure and low cardiac output with inotrope dependence. A non-significant hemodynamic improvement and an increase in the probability of successful dobutamine withdrawal were observed.
Acknowledgments
This study was sponsored by the São Paulo Research Foundation (FAPESP - grant number 2006/06463-9).
REFERENCES
-
1Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, et al. 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. Circulation. 2009;119(14):1977-2016.
-
2McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803-69.
-
3Ochiai ME, Cardoso JN, Vieira KR, Lima MV, Brancalhao EC, Barretto AC. Predictors of low cardiac output in decompensated severe heart failure. Clinics. 2011;66(2):239-44, http://dx.doi.org/10.1590/S1807-59322011000200010.
» http://dx.doi.org/10.1590/S1807-59322011000200010 -
4Johnson W, Omland T, Hall C, Lucas C, Myking OL, Collins C, et al. Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol. 2002;39(10):1623-9, http://dx.doi.org/10.1016/S0735-1097(02)01814-4.
» http://dx.doi.org/10.1016/S0735-1097(02)01814-4 -
5Mullens W, Abrahams Z, Francis GS, Sokos G, Starling RC, Young JB, et al. Usefulness of isosorbide dinitrate and hydralazine as add-on therapy in patients discharged for advanced decompensated heart failure. Am J Cardiol. 2009;103(8):1113-9, http://dx.doi.org/10.1016/j.amjcard.2008.12.028.
» http://dx.doi.org/10.1016/j.amjcard.2008.12.028 -
6Felker GM, Pang PS, Adams KF, Cleland JG, Cotter G, Dickstein K, et al. Clinical trials of pharmacological therapies in acute heart failure syndromes: lessons learned and directions forward. Circ Heart Fail. 2010;3(2):314-25, http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.893222.
» http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.893222 -
7Gheorghiade M, De Luca L, Fonarow GC, Filippatos G, Metra M, Francis GS. Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol. 2005;96(6A):11G-17G, http://dx.doi.org/10.1016/j.amjcard.2005.07.016.
» http://dx.doi.org/10.1016/j.amjcard.2005.07.016 -
8McMurray JJ, Östergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362(9386):767-71, http://dx.doi.org/10.1016/S0140-6736(03)14283-3.
» http://dx.doi.org/10.1016/S0140-6736(03)14283-3 -
9Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667-75.
-
10Cardoso J, Novaes M, Ochiai M, Regina K, Morgado P, Munhoz R, et al. Chagas cardiomyopathy: prognosis in clinical and hemodynamic profile C. Arq Bras Cardiol. 2010;95(4):518-23, http://dx.doi.org/10.1590/S0066-782X2010005000112.
» http://dx.doi.org/10.1590/S0066-782X2010005000112 -
11Ochiai ME, Barretto AC, Cardoso JN, Munhoz RT, Morgado PC, Ramires JA. Angiotensin II receptor blocker add-on therapy for low cardiac output in decompensated heart failure. Arq Bras Cardiol. 2010;94(2):219-22.
-
12Voyce SJ, Urbach D, Rippe JM. Pulmonary artery catheters. In: Rippe JM, Irwin RS, Alpert JS, Fink MP (eds). Intensive Care Medicine 2nd ed. Little, Boston: Brown and Company; 1991. p. 48-72.
-
13Diggle PJ. An approach to the analysis of repeated measurements. Biometrics. 1988;44(4):959-71, http://dx.doi.org/10.2307/2531727.
» http://dx.doi.org/10.2307/2531727 -
14Hosmer DW, Lemeshow S. Applied Logistic Regression. New York: Wiley. 1989.
-
15Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-81, http://dx.doi.org/10.1080/01621459.1958.10501452.
» http://dx.doi.org/10.1080/01621459.1958.10501452 -
16Cox DR, Oakes D. Analysis of Survival Data. 1st ed. London: Chapman and Hall. 1984.
-
17Cox DR. Regression Models and Life-tables. J Royal Statistical Society. 1972;34(2):187-220.
-
18Mitrovic V, Appel KF, Proskynitopoulos N, Dereli S, Hamm CW. Effects of candesartan cilexetil “add-on” treatment in congestive heart failure outpatients in daily practice. Clin Res Cardiol. 2009;98(6):379-89, http://dx.doi.org/10.1007/s00392-009-0011-7.
» http://dx.doi.org/10.1007/s00392-009-0011-7 -
19White M, Lepage S, Lavoie J, De Denus S, Leblanc MH, Gossard D, et al. Effects of combined candesartan and ACE inhibitors on BNP, markers of inflammation and oxidative stress, and glucose regulation in patients with symptomatic heart failure. J Card Fail. 2007;13(2):86-94, http://dx.doi.org/10.1016/j.cardfail.2006.10.013.
» http://dx.doi.org/10.1016/j.cardfail.2006.10.013 -
20Caccamo MA, Eckman PM. Pharmacologic therapy for New York Heart Association class IV heart failure. Congest Heart Fail. 2011;17(5):213-9, http://dx.doi.org/10.1111/j.1751-7133.2011.00235.x.
» http://dx.doi.org/10.1111/j.1751-7133.2011.00235.x -
21Packer M, Lee WH, Medina N, Yushak M, Kessler PD. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern Med. 1987;106(3):346-54, http://dx.doi.org/10.7326/0003-4819-106-3-346.
» http://dx.doi.org/10.7326/0003-4819-106-3-346 -
22Viecili PR, Pamplona D, Park M, Silva SR, Ramires JA, Da Luz PL. Antagonism of the acute hemodynamic effects of captopril in decompensated congestive heart failure by aspirin administration. Braz J Med Biol Res. 2003;36(6):771-80, http://dx.doi.org/10.1590/S0100-879X2003000600013.
» http://dx.doi.org/10.1590/S0100-879X2003000600013 -
23Tacon CL, McCaffrey J, Delaney A. Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials. Intensive Care Med. 2012;38(3):359-67, http://dx.doi.org/10.1007/s00134-011-2435-6.
» http://dx.doi.org/10.1007/s00134-011-2435-6 -
24Partovian C, Gleim SR, Mody PS, Li SX, Wang H, Strait KM, et al. Hospital patterns of use of positive inotropic agents in patients with heart failure. J Am Coll Cardiol. 2012;60(15):1402-9, http://dx.doi.org/10.1016/j.jacc.2012.07.011.
» http://dx.doi.org/10.1016/j.jacc.2012.07.011 -
25Follath F, Yilmaz MB, Delgado JF, Parissis JT, Porcher R, Gayat E, et al. Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). Intensive Care Med. 2011;37(4):619-26, http://dx.doi.org/10.1007/s00134-010-2113-0.
» http://dx.doi.org/10.1007/s00134-010-2113-0 -
26Mentz RJ, Felker GM. Natriuretic peptide-guided therapy for heart failure. Circ J. 2011;75(9):2031-7.
-
27Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;355(9210):1126-30, http://dx.doi.org/10.1016/S0140-6736(00)02060-2.
» http://dx.doi.org/10.1016/S0140-6736(00)02060-2 -
28Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal E, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol. 2007;49(16):1733-9, http://dx.doi.org/10.1016/j.jacc.2006.10.081.
» http://dx.doi.org/10.1016/j.jacc.2006.10.081 -
29Berger R, Moertl D, Peter S, Ahmadi R, Huelsmann M, Yamuti S, et al. N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3-arm, prospective, randomized pilot study. J Am Coll Cardiol. 2010;55(7):645-53, http://dx.doi.org/10.1016/j.jacc.2009.08.078.
» http://dx.doi.org/10.1016/j.jacc.2009.08.078 -
30Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374(9704):1840-8, http://dx.doi.org/10.1016/S0140-6736(09)61913-9.
» http://dx.doi.org/10.1016/S0140-6736(09)61913-9 -
31Cice G, Di Benedetto A, D'Isa S, D'Andrea A, Marcelli D, Gatti E, et al. Effects of telmisartan added to Angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure a double-blind, placebo-controlled trial. J Am Coll Cardiol. 2010;56(21):1701-8, http://dx.doi.org/10.1016/j.jacc.2010.03.105.
» http://dx.doi.org/10.1016/j.jacc.2010.03.105 -
32Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-59.
-
33Lakhdar R, Al-Mallah MH, Lanfear DE. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials. J Card Fail. 2008;14(3):181-8, http://dx.doi.org/10.1016/j.cardfail.2007.11.008.
» http://dx.doi.org/10.1016/j.cardfail.2007.11.008 -
34Ochiai ME, Barretto AC, Oliveira MT Jr, Munhoz RT, Morgado PC, Ramires JA. Uric acid renal excretion and renal insufficiency in decompensated severe heart failure. Eur J Heart Fail. 2005;7(4):468-74.
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No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
2014
History
-
Received
1 July 2013 -
Reviewed
8 Aug 2013 -
Accepted
27 Sept 2013