Miyuki Tsuchihashi-Makaya, Sanae Hamaguchi, Shintaro Kinugawa, Takashi Yokota, Daisuke Goto, Hisashi Yokoshiki, Norihiro Kato, Akira Takeshita, Hiroyuki Tsutsui, JCARE-CARD Investigators
Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
Circ J. 2009 Oct;73(10):1893-900. Epub 2009 Jul 31.
Abstract/Text
BACKGROUND: Heart failure (HF) with preserved ejection fraction (EF) is common. We compared the characteristics, treatments, and outcomes in HF patients with reduced vs preserved EF by using the national registry database in Japan.
METHODS AND RESULTS: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) is a prospective observational study in a broad sample of patients hospitalized with worsening HF. The study enrolled 2,675 patients from 164 hospitals with an average of 2.4 years of follow-up. Patients with preserved EF (EF >or=50% by echocardiography; n=429) were more likely to be older, female, have hypertension and atrial fibrillation, and less likely to have ischemic etiology compared with those with reduced EF (EF <40%; n=985). Unadjusted risk of in-hospital mortality (6.5% vs 3.9%; P=0.03) and post-discharge mortality (22.7% vs 17.8%; P=0.058) was slightly higher in patients with preserved EF, which, however, were not different after multivariable adjustment. Patients with preserved EF had similar rehospitalization rates (36.2% vs 33.4%; P=0.515) compared with patients with reduced EF.
CONCLUSIONS: HF patients with preserved EF had a similar mortality risk and equally high rates of rehospitalization as those with reduced EF. Effective management strategies are critically needed to be established for this type of HF.
Nobuyuki Shiba, Jun Watanabe, Tsuyoshi Shinozaki, Yoshito Koseki, Masahito Sakuma, Yutaka Kagaya, Kunio Shirato, CHART Investigators
Analysis of chronic heart failure registry in the Tohoku district: third year follow-up.
Circ J. 2004 May;68(5):427-34.
Abstract/Text
BACKGROUND: Because the real prognosis of Japanese patients with chronic heart failure (CHF) is still unknown, the aim of the present study was to clarify the prognosis and predictors for mortality of CHF patients using the Chronic Heart failure Analysis and Registry in Tohoku district (CHART).
METHODS AND RESULTS: As of February 2003, 1,154 stable CHF patients with optimum standard therapy have been enrolled in the registry since February 2000 and of these, 175 died of some cause during the follow-up period (mean follow-up period, 1.9+/-0.9 years), giving 1- and 3-year all-cause mortality rates of 7.3% and 20.9%, respectively. Multivariate analysis showed that age at entry, diabetes, ventricular tachycardia, plasma concentration of brain natriuretic peptide (BNP), New York Heart Association (NYHA) functional class and rural residence were significantly associated with all-cause mortality (hazard ratio: 1.028, 1.940, 1.650, 1.001, 1.713, and 2.226). The 1-year all-cause mortality rates of CHF patients with a left ventricular ejection fraction <25%, left ventricular end-diastolic diameter > or =60 mm, BNP > or =500 pg/ml, NYHA > or = III, or with underlying coronary artery disease were 15.0%, 11.4%, 16.8%, 16.3%, and 10.8%, respectively.
CONCLUSIONS: The prognosis of Japanese CHF patients with these predictors remains poor. A stratified approach is necessary to improve their survival and quality of life.
Nobuyuki Shiba, Kotaro Nochioka, Masanobu Miura, Haruka Kohno, Hiroaki Shimokawa, CHART-2 Investigators
Trend of westernization of etiology and clinical characteristics of heart failure patients in Japan--first report from the CHART-2 study.
Circ J. 2011;75(4):823-33. Epub 2011 Mar 20.
Abstract/Text
BACKGROUND: Hospitalization due to acute heart failure syndrome (AHFS) is an indicator of worsened prognosis for patients with cardiovascular disease (CVD). The Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study was designed to elucidate characteristics and prognosis of patients at high risk for CVD progression due to AHFS.
METHODS AND RESULTS: The CHART-2 Study is a prospective observational multicenter cohort study. Patients with overt HF, structural cardiac disorder but without HF, or with coronary artery disease (CAD) have been consecutively enrolled from October 2006. As of March 2010, a total of 10,219 patients have been recruited, making the Study the largest multicenter prospective cohort of HF patients in Japan. The mean patient age was 68.2±12.3 years and male patients accounted for 69.8%. Overt HF was observed in 46.3% of patients; and 53.7% did not have HF but were at high risk for AHFS. As HF stage progressed, the prognostic risks (eg, chronic kidney disease, reduced ejection fraction, and increased B-type natriuretic peptide level) became more prominent. Compared with the previous CHART-1 study, the prevalence of ischemic etiology and risk factors (hypertension, diabetes) have increased, as in Western studies.
CONCLUSIONS: This first report demonstrates the trend of westernization of ischemic etiology and clinical characteristics of HF patients in Japan, indicating the importance of appropriate management and prevention of CAD to prevent AHFS.
All rights are reserved to the Japanese Circulation Society.
Hiroyuki Tsutsui, Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Daisuke Goto, Akira Takeshita, JCARE-GENERAL Investigators
Characteristics and outcomes of patients with heart failure in general practices and hospitals.
Circ J. 2007 Apr;71(4):449-54.
Abstract/Text
BACKGROUND: The characteristics and outcomes of patients discharged from hospitals with a diagnosis of heart failure (HF) have been described by a number of previous epidemiological studies. However, very little information is available on this issue in general practice in Japan.
METHODS AND RESULTS: The Japanese Cardiac Registry of Heart Failure in General Practice (JCARE-GENERAL) is designed to study the characteristics, treatment and outcomes prospectively in a broad sample of outpatients with HF who were managed by cardiologists in hospital (Hospital-HF) and primary care physicians in general practice (GP-HF). Out of 2,685 patients with HF, 1,280 patients were Hospital-HF and 1,405 GP-HF. Compared to the Hospital-HF patients, GP-HF patients were more likely to be elderly and female, and they had a higher prevalence of hypertensive heart disease as a cause of HF. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and beta-blockers were more prescribed to Hospital-HF than GP-HF patients. At the follow-up of 1.2 year, after adjustment, the mortality was comparable between the Hospital-HF and GP-HF groups, whereas HF-related admission was higher in the Hospital-HF group than in in the GP-HF group.
CONCLUSIONS: Based on the JCARE-GENERAL, the characteristics, treatment and outcomes of GP-HF patients differed from those of Hospital-HFpatients in Japan.
G Michael Felker, Vic Hasselblad, Adrian F Hernandez, Christopher M O'Connor
Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials.
Am Heart J. 2009 Sep;158(3):422-30. doi: 10.1016/j.ahj.2009.06.018. Epub 2009 Jul 9.
Abstract/Text
BACKGROUND: Measurement of circulating natriuretic peptides has been shown to play an important role in diagnosis and prognosis in patients with chronic heart failure. Whether serial natriuretic peptide measurements to aid in the titration of therapy can improve heart failure outcomes remains uncertain. We performed a quantitative meta-analysis of available randomized controlled trials to determine whether titration of therapy based on natriuretic peptide measurements improves mortality in chronic heart failure.
METHODS: We identified potentially relevant studies through a search of MEDLINE (1996-2009), ISI Web of Knowledge (1996-2009), Cochrane Central Register of Controlled Trials (1996-2009), clinicaltrials.gov, proceedings of major US and European cardiology meetings (2000-2009), and bibliographic review of secondary sources. Search terms were "biomarker," "natriuretic peptide," "B-type natriuretic peptide," "N-terminal B-type natriuretic peptide," and "heart failure." Studies were included if they were prospective, randomized controlled trials of patients with chronic heart failure, they randomized patients to a strategy of titrating medical therapy based on the level of a circulating biomarker compared to a parallel control group, and they reported all-cause mortality.
RESULTS: Six studies randomizing 1627 patients met criteria for inclusion. Pooled analysis showed a significant mortality advantage for biomarker-guided therapy (hazard ratio was 0.69, 95% CI 0.55-0.86) compared to control. There was no quantitative evidence of heterogeneity between studies (P = .42).
CONCLUSIONS: Titration of therapy incorporating serial BNP or N-terminal pro-B-type natriuretic peptide levels is associated with a significant reduction in all-cause mortality compared to usual care in patients with chronic heart failure.
Pramote Porapakkham, Pornwalee Porapakkham, Hendrik Zimmet, Baki Billah, Henry Krum
B-type natriuretic peptide-guided heart failure therapy: A meta-analysis.
Arch Intern Med. 2010 Mar 22;170(6):507-14. doi: 10.1001/archinternmed.2010.35.
Abstract/Text
BACKGROUND: The use of plasma levels of B-type natriuretic peptides (BNPs) to guide treatment of patients with chronic heart failure (HF) has been investigated in a number of randomized controlled trials (RCTs). However, the benefits of this treatment approach have been uncertain. We therefore performed a meta-analysis to examine the overall effect of BNP-guided drug therapy on cardiovascular outcomes in patients with chronic HF.
METHODS: We identified RCTs by systematic search of manuscripts, abstracts, and databases. Eligible RCTs were those that enrolled more than 20 patients and involved comparison of BNP-guided drug therapy vs usual clinical care of the patient with chronic HF in an outpatient setting.
RESULTS: Eight RCTs with a total of 1726 patients and with a mean duration of 16 months (range, 3-24 months) were included in the meta-analysis. Overall, there was a significantly lower risk of all-cause mortality (relative risk [RR], 0.76; 95% confidence interval [CI], 0.63-0.91; P = .003) in the BNP-guided therapy group compared with the control group. In the subgroup of patients younger than 75 years, all-cause mortality was also significantly lower in the BNP-guided group (RR, 0.52; 95% CI, 0.33-0.82; P = .005). However, there was no reduction in mortality with BNP-guided therapy in patients 75 years or older (RR, 0.94; 95% CI, 0.71-1.25; P = .70). The risk of all-cause hospitalization and survival free of any hospitalization was not significantly different between groups (RR, 0.82; 95% CI, 0.64-1.05; P = .12 and RR, 1.07; 95% CI, 0.85-1.34; P = .58, respectively). The additional percentage of patients achieving target doses of angiotensin-converting enzyme inhibitors and beta-blockers during the course of these trials averaged 21% and 22% in the BNP group and 11.7% and 12.5% in the control group, respectively.
CONCLUSIONS: B-type natriuretic peptide-guided therapy reduces all-cause mortality in patients with chronic HF compared with usual clinical care, especially in patients younger than 75 years. A component of this survival benefit may be due to increased use of agents proven to decrease mortality in chronic HF. However, there does not seem to be a reduction in all-cause hospitalization or an increase in survival free of hospitalization using this approach.
Matthias Pfisterer, Peter Buser, Hans Rickli, Marc Gutmann, Paul Erne, Peter Rickenbacher, André Vuillomenet, Urs Jeker, Paul Dubach, Hansjürg Beer, Se-Il Yoon, Thomas Suter, Hans H Osterhues, Michael M Schieber, Patrick Hilti, Ruth Schindler, Hans-Peter Brunner-La Rocca, TIME-CHF Investigators
BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial.
JAMA. 2009 Jan 28;301(4):383-92. doi: 10.1001/jama.2009.2.
Abstract/Text
CONTEXT: It is uncertain whether intensified heart failure therapy guided by N-terminal brain natriuretic peptide (BNP) is superior to symptom-guided therapy.
OBJECTIVE: To compare 18-month outcomes of N-terminal BNP-guided vs symptom-guided heart failure therapy.
DESIGN, SETTING, AND PATIENTS: Randomized controlled multicenter Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) of 499 patients aged 60 years or older with systolic heart failure (ejection fraction < or = 45%), New York Heart Association (NYHA) class of II or greater, prior hospitalization for heart failure within 1 year, and N-terminal BNP level of 2 or more times the upper limit of normal. The study had an 18-month follow-up and it was conducted at 15 outpatient centers in Switzerland and Germany between January 2003 and June 2008.
INTERVENTION: Uptitration of guideline-based treatments to reduce symptoms to NYHA class of II or less (symptom-guided therapy) and BNP level of 2 times or less the upper limit of normal and symptoms to NYHA class of II or less (BNP-guided therapy).
MAIN OUTCOME MEASURES: Primary outcomes were 18-month survival free of all-cause hospitalizations and quality of life as assessed by structured validated questionnaires.
RESULTS: Heart failure therapy guided by N-terminal BNP and symptom-guided therapy resulted in similar rates of survival free of all-cause hospitalizations (41% vs 40%, respectively; hazard ratio [HR], 0.91 [95% CI, 0.72-1.14]; P = .39). Patients' quality-of-life metrics improved over 18 months of follow-up but these improvements were similar in both the N-terminal BNP-guided and symptom-guided strategies. Compared with the symptom-guided group, survival free of hospitalization for heart failure, a secondary end point, was higher among those in the N-terminal BNP-guided group (72% vs 62%, respectively; HR, 0.68 [95% CI, 0.50-0.92]; P = .01). Heart failure therapy guided by N-terminal BNP improved outcomes in patients aged 60 to 75 years but not in those aged 75 years or older (P < .02 for interaction)
CONCLUSION: Heart failure therapy guided by N-terminal BNP did not improve overall clinical outcomes or quality of life compared with symptom-guided treatment.
TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN43596477.
John G Lainchbury, Richard W Troughton, Kim M Strangman, Christopher M Frampton, Anna Pilbrow, Timothy G Yandle, Amjad K Hamid, M Gary Nicholls, A Mark Richards
N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial.
J Am Coll Cardiol. 2009 Dec 29;55(1):53-60. doi: 10.1016/j.jacc.2009.02.095.
Abstract/Text
OBJECTIVES: The purpose of this study was to compare the effects of N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided therapy with those of intensive clinical management and with usual care (UC) on clinical outcomes in chronic symptomatic heart failure.
BACKGROUND: Initial trial results suggest titration of therapy guided by serial plasma B-type natriuretic peptide levels improves outcomes in patients with chronic heart failure, but the concept has not received widespread acceptance. Accordingly, we conducted a longer-term study comparing the effects of NT-proBNP-guided therapy with those of intensive clinical management and with UC of patients with heart failure.
METHODS: Three hundred sixty-four patients admitted to a single hospital with heart failure were randomly allocated 1:1:1 (stratified by age) to therapy guided by NT-proBNP levels or by intensive clinical management, or according to UC. Treatment strategies were applied for 2 years with follow-up to 3 years.
RESULTS: One-year mortality was less in both the hormone- (9.1%) and clinically-guided (9.1%) groups compared with UC (18.9%; p = 0.03). Three-year mortality was selectively reduced in patients CONCLUSIONS: Intensive management of chronic heart failure improves 1-year mortality compared with UC. Compared with clinically guided treatment and UC, hormone-guided treatment selectively improves longer-term mortality in patients
Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Patric Karlström, Urban Alehagen, Kurt Boman, Ulf Dahlström, UPSTEP-study group
Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome.
Eur J Heart Fail. 2011 Oct;13(10):1096-103. doi: 10.1093/eurjhf/hfr078. Epub 2011 Jun 29.
Abstract/Text
AIM: To determine whether brain natriuretic peptide (BNP)-guided heart failure (HF) treatment improves morbidity and/or mortality when compared with conventional treatment.
METHODS AND RESULTS: UPSTEP was an investigator-initiated, randomized, parallel group, multicentre study with a PROBE design. Symptomatic patients with worsening HF, New York Heart Association class II-IV, ejection fraction <40% and elevated BNP levels, were included. All patients (n= 279) were treated according to recommended guidelines and randomized to BNP-guided (BNP) or to conventional (CTR) HF treatment. The goal was to reduce BNP levels to <150 ng/L in younger patients and <300 ng/L in elderly patients, respectively. The primary outcome was a composite of death due to any cause, need for hospitalization and worsening HF. The study groups were well matched, including for BNP concentration at entry (mean: 808 vs. 899 ng/L; P= 0.34). There were no significant differences between the groups regarding either the primary outcome (P = 0.18) or any of the secondary endpoints. There were no differences for the pre-specified analyses; days out of hospital, and younger vs. elderly. A subgroup analysis comparing treatment responders (>30% decrease in baseline BNP value) vs. non-responders found improved survival among responders (P< 0.0001 for the primary outcome), and all of the secondary endpoints were also improved.
CONCLUSIONS: Morbidity and mortality were not improved by HF treatment guided by BNP levels. However, BNP responders had a significantly better clinical outcome than non-responders. Future research is needed to elucidate the responsible pathophysiological mechanisms in this sub-population.
Rudolf Berger, Deddo Moertl, Sieglinde Peter, Roozbeh Ahmadi, Martin Huelsmann, Susan Yamuti, Brunhilde Wagner, Richard Pacher
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 Feb 16;55(7):645-53. doi: 10.1016/j.jacc.2009.08.078.
Abstract/Text
OBJECTIVES: This study was designed to investigate whether the addition of N-terminal pro-B-type natriuretic peptide-guided, intensive patient management (BM) to multidisciplinary care (MC) improves outcome in patients following hospitalization due to heart failure (HF).
BACKGROUND: Patients hospitalized due to HF experience frequent rehospitalizations and high mortality.
METHODS: Patients hospitalized due to HF were randomized to BM, MC, or usual care (UC). Multidisciplinary care included 2 consultations from an HF specialist who provided therapeutic recommendations and home care by a specialized HF nurse. In addition, BM included intensified up-titration of medication by HF specialists in high-risk patients. NT-proBNP was used to define the level of risk and to monitor wall stress. This monitoring allowed for anticipation of cardiac decompensation and adjustment of medication in advance.
RESULTS: A total of 278 patients were randomized in 8 Viennese hospitals. After 12 months, the BM group had the highest proportion of antineurohormonal triple-therapy (difference among all groups). Accordingly, BM reduced days of HF hospitalization (488 days) compared with the hospitalization for the MC (1,254 days) and UC (1,588 days) groups (p < 0.0001; significant differences among all groups). Using Kaplan-Meier analysis, the first HF rehospitalization (28%) was lower in the BM versus MC groups (40%; p = 0.06) and the MC versus UC groups (61%; p = 0.01). Moreover, the combined end point of death or HF rehospitalization was lower in the BM (37%) than in the MC group (50%; p < 0.05) and in the MC than in the UC group (65%; p = 0.04). Death rate was similar between the BM (22%) and MC groups (22%), but was lower compared with the UC group (39%; vs. BM: p < 0.02; vs. MC: p < 0.02).
CONCLUSIONS: Compared with MC alone, additional BM improves clinical outcome in patients after HF hospitalization. (BNP Guided Care in Addition to Multidisciplinary Care; NCT00355017).
Faiez Zannad, John J V McMurray, Henry Krum, Dirk J van Veldhuisen, Karl Swedberg, Harry Shi, John Vincent, Stuart J Pocock, Bertram Pitt, EMPHASIS-HF Study Group
Eplerenone in patients with systolic heart failure and mild symptoms.
N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJMoa1009492. Epub 2010 Nov 14.
Abstract/Text
BACKGROUND: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms.
METHODS: In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.
RESULTS: The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).
CONCLUSIONS: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).
John J V McMurray
Clinical practice. Systolic heart failure.
N Engl J Med. 2010 Jan 21;362(3):228-38. doi: 10.1056/NEJMcp0909392.
Abstract/Text
Tohru Masuyama, Takeshi Tsujino, Hideki Origasa, Kazuhiro Yamamoto, Takashi Akasaka, Yutaka Hirano, Nobuyuki Ohte, Takashi Daimon, Satoshi Nakatani, Hiroshi Ito
Superiority of long-acting to short-acting loop diuretics in the treatment of congestive heart failure.
Circ J. 2012;76(4):833-42.
Abstract/Text
BACKGROUND: Diuretics are the most prescribed drug in heart failure (HF) patients. However, clinical evidence about their long-term effects is lacking. The purpose of this study was to compare the therapeutic effects of furosemide and azosemide, a short- and long-acting loop diuretic, respectively, in patients with chronic heart failure (CHF).
METHODS AND RESULTS: In this multicenter, prospective, randomized, open, blinded endpoint trial, we compared the effects of azosemide and furosemide in patients with CHF and New York Heart Association class II or III symptoms. 320 patients (160 patients in each group, mean age 71 years) were followed up for a minimum of 2 years. The primary endpoint was a composite of cardiovascular death or unplanned admission to hospital for congestive HF. During a median follow-up of 35.2 months, the primary endpoint occurred in 23 patients in the azosemide group and in 34 patients in the furosemide group (hazard ratio [HR], 0.55, 95% confidence interval [CI] 0.32-0.95: P=0.03). Among the secondary endpoints, unplanned admission to hospital for congestive HF or a need for modification of the treatment for HF were also reduced in the azosemide group compared with the furosemide group (HR, 0.60, 95%CI 0.36-0.99: P=0.048).
CONCLUSIONS: Azosemide, compared with furosemide, reduced the risk of cardiovascular death or unplanned admission to hospital for congestive HF.
Mariann R Piano, Marilyn A Prasun, Thomas Stamos, Vicki Groo
Flexible diuretic titration in chronic heart failure: where is the evidence?
J Card Fail. 2011 Nov;17(11):944-54. doi: 10.1016/j.cardfail.2011.10.001.
Abstract/Text
BACKGROUND: Several sets of heart failure (HF) consensus/guideline statements support the use of a flexible diuretic dosing regimen for HF outpatient management of fluid overload-related signs and symptoms. However, despite the widespread acceptance of such an approach, the evidence supporting the effectiveness of this approach in improving clinical outcomes is unknown. The primary objective of this manuscript was to summarize and review the evidence supporting the use of a flexible diuretic regimen in the management of outpatient heart failure patients.
METHODS AND RESULTS: A systematic review was performed, and 9 studies were identified relevant to the question of flexible diuretic titration in the setting of chronic heart failure. Among the 9 studies, 5 were randomized. Three of the randomized trials included flexible diuretic titration as part of a broader multifaceted disease management program, and only 2 were designed to specifically evaluate the sole contribution of flexible diuretic titration. Collectively, data from all of the studies reviewed supported the idea that flexible and individualized diuretic dosing is potentially associated with reduced emergency room visits, reduced rehospitalization, and improved quality of life in HF patients with reduced ejection fraction.
CONCLUSIONS: To date, only 2 randomized clinical studies were identified that were designed to determine the effects of a flexible diuretic dosing regimen in outpatient HF patients with reduced ejection fraction. Data are lacking in HF patients with preserved ejection fraction. There is a critical need to test this strategy in well designed prospective randomized clinical trials.
Copyright © 2011 Elsevier Inc. All rights reserved.
Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
N Engl J Med. 1987 Jun 4;316(23):1429-35. doi: 10.1056/NEJM198706043162301.
Abstract/Text
To evaluate the influence of the angiotensin-converting-enzyme inhibitor enalapril (2.5 to 40 mg per day) on the prognosis of severe congestive heart failure (New York Heart Association [NYHA] functional class IV), we randomly assigned 253 patients in a double-blind study to receive either placebo (n = 126) or enalapril (n = 127). Conventional treatment for heart failure, including the use of other vasodilators, was continued in both groups. Follow-up averaged 188 days (range, 1 day to 20 months). The crude mortality at the end of six months (primary end point) was 26 percent in the enalapril group and 44 percent in the placebo group--a reduction of 40 percent (P = 0.002). Mortality was reduced by 31 percent at one year (P = 0.001). By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group--a reduction of 27 percent (P = 0.003). The entire reduction in total mortality was found to be among patients with progressive heart failure (a reduction of 50 percent), whereas no difference was seen in the incidence of sudden cardiac death. A significant improvement in NYHA classification was observed in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for heart failure. The overall withdrawal rate was similar in both groups, but hypotension requiring withdrawal occurred in seven patients in the enalapril group and in no patients in the placebo group. After the initial dose of enalapril was reduced to 2.5 mg daily in high-risk patients, this side effect was less frequent. We conclude that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The beneficial effect on mortality is due to a reduction in death from the progression of heart failure.
Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
N Engl J Med. 1991 Aug 1;325(5):293-302. doi: 10.1056/NEJM199108013250501.
Abstract/Text
BACKGROUND: Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting-enzyme inhibitor, enalapril, on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35.
METHODS: Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5 to 20 mg per day in a double-bind trial. Approximately 90 percent of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months.
RESULTS: There were 510 deaths in the placebo group (39.7 percent), as compared with 452 in the enalapril group (35.2 percent) (reduction in risk, 16 percent; 95 percent confidence interval, 5 to 26 percent; P = 0.0036). Although reductions in mortality were observed in several categories of cardiac deaths, the largest reduction occurred among the deaths attributed to progressive heart failure (251 in the placebo group vs. 209 in the enalapril group; reduction in risk, 22 percent; 95 percent confidence interval, 6 to 35 percent). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26 percent; 95 percent confidence interval, 18 to 34 percent; P less than 0.0001).
CONCLUSIONS: The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions.
Ronnie Willenheimer, Dirk J van Veldhuisen, Bernard Silke, Erland Erdmann, Ferenc Follath, Henry Krum, Piotr Ponikowski, Allan Skene, Louis van de Ven, Patricia Verkenne, Philippe Lechat, CIBIS III Investigators
Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III.
Circulation. 2005 Oct 18;112(16):2426-35. doi: 10.1161/CIRCULATIONAHA.105.582320. Epub 2005 Sep 4.
Abstract/Text
BACKGROUND: In patients with chronic heart failure (CHF), a beta-blocker is generally added to a regimen containing an angiotensin-converting-enzyme (ACE) inhibitor. It is unknown whether beta-blockade as initial therapy may be as useful.
METHODS AND RESULTS: We randomized 1010 patients with mild to moderate CHF and left ventricular ejection fraction < or =35%, who were not receiving ACE inhibitor, beta-blocker, or angiotensin receptor blocker therapy, to open-label monotherapy with either bisoprolol (target dose 10 mg QD; n=505) or enalapril (target dose 10 mg BID; n=505) for 6 months, followed by their combination for 6 to 24 months. The 2 strategies were blindly compared with regard to the combined primary end point of all-cause mortality or hospitalization and with regard to each of these end point components individually. Bisoprolol-first treatment was noninferior to enalapril-first treatment if the upper limit of the 95% confidence interval (CI) for the absolute between-group difference was <5%, corresponding to a hazard ratio (HR) of 1.17. In the intention-to-treat sample, the primary end point occurred in 178 patients allocated to bisoprolol-first treatment versus 186 allocated to enalapril-first treatment (absolute difference -1.6%, 95% CI -7.6 to 4.4%, HR 0.94; 95% CI 0.77 to 1.16). In the per-protocol sample, 163 patients allocated to bisoprolol-first treatment had a primary end point, versus 165 allocated to enalapril-first treatment (absolute difference -0.7%, 95% CI -6.6 to 5.1%, HR 0.97; 95% CI 0.78 to 1.21). With bisoprolol-first treatment, 65 patients died, versus 73 with enalapril-first treatment (HR 0.88; 95% CI 0.63 to 1.22), and 151 versus 157 patients were hospitalized (HR 0.95; 95% CI 0.76 to 1.19).
CONCLUSIONS: Although noninferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, our results indicate that it may be as safe and efficacious to initiate treatment for CHF with bisoprolol as with enalapril.
M Packer, A J Coats, M B Fowler, H A Katus, H Krum, P Mohacsi, J L Rouleau, M Tendera, A Castaigne, E B Roecker, M K Schultz, D L DeMets, Carvedilol Prospective Randomized Cumulative Survival Study Group
Effect of carvedilol on survival in severe chronic heart failure.
N Engl J Med. 2001 May 31;344(22):1651-8. doi: 10.1056/NEJM200105313442201.
Abstract/Text
BACKGROUND: Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure.
METHODS: We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded.
RESULTS: There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.00013, unadjusted; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol (95 percent confidence interval, 13 to 33 percent; P<0.001). The favorable effects on both end points were seen consistently in all the subgroups we examined, including patients with a history of recent or recurrent cardiac decompensation. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (P=0.02).
CONCLUSIONS: The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial.
Masatsugu Hori, Shigetake Sasayama, Akira Kitabatake, Teruhiko Toyo-oka, Shunnosuke Handa, Mitsuhiro Yokoyama, Masunori Matsuzaki, Akira Takeshita, Hideki Origasa, Kennichi Matsui, Saichi Hosoda, MUCHA Investigators
Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial.
Am Heart J. 2004 Feb;147(2):324-30. doi: 10.1016/j.ahj.2003.07.023.
Abstract/Text
BACKGROUND: The efficacy and optimum dose of beta-blockers have not been established in Japanese patients with chronic heart failure (CHF). The efficacy and safety of two doses of carvedilol, a beta-blocker with vasodilator and antioxidant actions, were investigated in Japanese patients with CHF.
METHODS: After screening and a carvedilol challenge phase, 174 patients with mild to moderate CHF were randomly assigned (double-blinded) to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. After a 2- to 4-week uptitration phase, maintenance treatment was continued for 24 to 48 weeks. The primary end point was improvement of the global assessment of CHF by the attending physician. Secondary end points were death or hospitalization for cardiovascular disease, cardiovascular hospitalization, hospitalization for heart failure, change of left ventricular ejection fraction, and change in New York Heart Association class.
RESULTS: Carvedilol therapy achieved dose-dependent improvement of all end points (P for linear trend, range.002 to <.001). Both carvedilol groups showed marked risk reduction (71% to 91%) for cardiovascular and CHF hospitalization and for death or cardiovascular hospitalization (P range,.024 to <.001 for pairwise comparisons with placebo). No significant differences were observed for noncardiovascular hospitalization or adverse events.
CONCLUSIONS: In Japanese patients with mild or moderate CHF, carvedilol achieved dose-related improvement of CHF and left ventricular ejection fraction; cardiovascular hospitalization was markedly reduced. At 5 mg/d, carvedilol conferred an important patient benefit, less than at 20 mg/d.
JoAnne Micale Foody, Michael H Farrell, Harlan M Krumholz
beta-Blocker therapy in heart failure: scientific review.
JAMA. 2002 Feb 20;287(7):883-9.
Abstract/Text
CONTEXT: Care of patients with heart failure has been revolutionized throughout the past decade. A paradigm shift in the strategy for treating heart failure caused by systolic dysfunction is in progress. Despite the initial perception about beta-blockers' safety, they are now the most extensively studied class of agents in the treatment of heart failure and have emerged as an important intervention to improve the clinical outcomes of heart failure patients.
OBJECTIVE: To provide scientific rationale for the use of beta-blockers for patients with heart failure.
DATA SOURCES: All English-language articles of large, randomized controlled clinical trials assessing the mortality benefits of beta-blockers in patients with heart failure were identified to provide the scientific rationale for the use of beta-blockers in heart failure. Basic science studies were reviewed to provide an overview of the potential physiologic role of beta-blockers in heart failure. Finally, clinical guidelines for the treatment of patients with heart failure were assessed to determine current recommendations for the use of these agents.
STUDY SELECTION AND DATA EXTRACTION: Randomized controlled clinical trials of beta-blockers that included more than 300 subjects and assessed mortality as a primary end point.
DATA SYNTHESIS: Of the 4 beta-blockers tested in large randomized controlled clinical trials of patients with heart failure, 3 are available in the United States, bisoprolol, carvedilol, and metoprolol; 2 of these, carvedilol and metoprolol, have Food and Drug Administration indications for the treatment of heart failure. Compared with placebo treatment, beta-blocker use is associated with a consistent 30% reduction in mortality and a 40% reduction in hospitalizations in patients with class II and III heart failure.
CONCLUSIONS: Tested in more than 10,000 patients, beta-blockers reduce morbidity and mortality in class II through IV heart failure. Along with angiotensin-converting enzyme inhibitors, digoxin, and diuretics, beta-blockers have strengthened the armamentarium to improve clinical outcomes of heart failure patients. The science supporting beta-blockers must be translated into practice safely and rationally if the agents are to achieve their full potential.
Philip B Adamson, Edward M Gilbert
Reducing the risk of sudden death in heart failure with beta-blockers.
J Card Fail. 2006 Dec;12(9):734-46. doi: 10.1016/j.cardfail.2006.08.213.
Abstract/Text
BACKGROUND: Heart failure (HF) is a serious cardiovascular syndrome that affects nearly 5 million people in the United States. A review of clinical data demonstrates that sudden cardiac death (SCD) accounts for approximately one-third of all HF deaths. This fatal outcome typically involves an unexpected electrical event leading to sustained cardiac arrhythmias resulting in cardiovascular collapse.
METHODS AND RESULTS: A systematic review of the literature was performed to serve as the basis for this review. Factors contributing directly to incidence of SCD in the HF population may include significant remodeling of the left ventricle (hypertrophy, dilation, and fibrosis) in addition to increased sympathetic activation. Using specific therapies to limit these mechanisms are beneficial in the HF patient by preventing SCD. Beta-blockers play a key role in the prevention of SCD for patients with HF by limiting the effects of circulating norepinephrine and by reducing left ventricular remodeling.
CONCLUSIONS: This review outlines the potential mechanisms and contributing factors of SCD in patients with HF and the impact of beta-blocker usage in the prevention of this fatal outcome for this growing patient population.
Nassir F Marrouche, Johannes Brachmann, Dietrich Andresen, Jürgen Siebels, Lucas Boersma, Luc Jordaens, Béla Merkely, Evgeny Pokushalov, Prashanthan Sanders, Jochen Proff, Heribert Schunkert, Hildegard Christ, Jürgen Vogt, Dietmar Bänsch, CASTLE-AF Investigators
Catheter Ablation for Atrial Fibrillation with Heart Failure.
N Engl J Med. 2018 Feb 1;378(5):417-427. doi: 10.1056/NEJMoa1707855.
Abstract/Text
BACKGROUND: Mortality and morbidity are higher among patients with atrial fibrillation and heart failure than among those with heart failure alone. Catheter ablation for atrial fibrillation has been proposed as a means of improving outcomes among patients with heart failure who are otherwise receiving appropriate treatment.
METHODS: We randomly assigned patients with symptomatic paroxysmal or persistent atrial fibrillation who did not have a response to antiarrhythmic drugs, had unacceptable side effects, or were unwilling to take these drugs to undergo either catheter ablation (179 patients) or medical therapy (rate or rhythm control) (184 patients) for atrial fibrillation in addition to guidelines-based therapy for heart failure. All the patients had New York Heart Association class II, III, or IV heart failure, a left ventricular ejection fraction of 35% or less, and an implanted defibrillator. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure.
RESULTS: After a median follow-up of 37.8 months, the primary composite end point occurred in significantly fewer patients in the ablation group than in the medical-therapy group (51 patients [28.5%] vs. 82 patients [44.6%]; hazard ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.87; P=0.007). Significantly fewer patients in the ablation group died from any cause (24 [13.4%] vs. 46 [25.0%]; hazard ratio, 0.53; 95% CI, 0.32 to 0.86; P=0.01), were hospitalized for worsening heart failure (37 [20.7%] vs. 66 [35.9%]; hazard ratio, 0.56; 95% CI, 0.37 to 0.83; P=0.004), or died from cardiovascular causes (20 [11.2%] vs. 41 [22.3%]; hazard ratio, 0.49; 95% CI, 0.29 to 0.84; P=0.009).
CONCLUSIONS: Catheter ablation for atrial fibrillation in patients with heart failure was associated with a significantly lower rate of a composite end point of death from any cause or hospitalization for worsening heart failure than was medical therapy. (Funded by Biotronik; CASTLE-AF ClinicalTrials.gov number, NCT00643188 .).
Tetsuo Yamaguchi, Takeshi Kitai, Takamichi Miyamoto, Nobuyuki Kagiyama, Takahiro Okumura, Keisuke Kida, Shogo Oishi, Eiichi Akiyama, Satoshi Suzuki, Masayoshi Yamamoto, Junji Yamaguchi, Takamasa Iwai, Sadahiro Hijikata, Ryo Masuda, Ryoichi Miyazaki, Nobuhiro Hara, Yasutoshi Nagata, Toshihiro Nozato, Yuya Matsue
Effect of Optimizing Guideline-Directed Medical Therapy Before Discharge on Mortality and Heart Failure Readmission in Patients Hospitalized With Heart Failure With Reduced Ejection Fraction.
Am J Cardiol. 2018 Apr 15;121(8):969-974. doi: 10.1016/j.amjcard.2018.01.006. Epub 2018 Feb 21.
Abstract/Text
Guideline-directed medical therapy (GDMT) is recommended for patients with heart failure with reduced ejection fraction (HFrEF). However, the prognostic impact of medication optimization at the time of discharge in patients hospitalized with heart failure (HF) is unclear. We analyzed 534 patients (73 ± 13 years old) with HFrEF. The status of GDMT at the time of discharge (prescription of angiotensin converting enzyme inhibitor [ACE-I]/angiotensin receptor blocker [ARB] and β blocker [BB]) and its association with 1-year all-cause mortality and HF readmission were investigated. Patients were divided into 3 groups: those treated with both ACE-I/ARB and BB (Both group: n = 332, 62%), either ACE-I/ARB or BB (Either group: n = 169, 32%), and neither ACE-I/ARB nor BB (None group: n = 33, 6%), respectively. One-year mortality, but not 1-year HF readmission rate, was significantly different in the 3 groups, in favor of the Either and Both groups. A favorable impact of being on GDMT at the time of discharge on 1-year mortality was retained even after adjustment for covariates (Either group: hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.21 to 0.90, p = 0.025 and Both group: HR 0.29, 95% CI 0.13-0.65, p = 0.002, vs None group). For 1-year HF readmission, no such association was found. In conclusion, optimization of GDMT before the time of discharge was associated with a lower 1-year mortality, but not with HF readmission rate, in patients hospitalized with HFrEF.
Copyright © 2018 Elsevier Inc. All rights reserved.
Lynne Warner Stevenson
Beta-blockers for stable heart failure.
N Engl J Med. 2002 May 2;346(18):1346-7. doi: 10.1056/NEJM200205023461802.
Abstract/Text
B Pitt, P A Poole-Wilson, R Segal, F A Martinez, K Dickstein, A J Camm, M A Konstam, G Riegger, G H Klinger, J Neaton, D Sharma, B Thiyagarajan
Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II.
Lancet. 2000 May 6;355(9215):1582-7.
Abstract/Text
BACKGROUND: The ELITE study showed an association between the angiotensin II antagonist losartan and an unexpected survival benefit in elderly heart-failure patients, compared with captopril, an angiotensin-converting-enzyme (ACE) inhibitor. We did the ELITE II Losartan Heart Failure Survival Study to confirm whether losartan is superior to captopril in improving survival and is better tolerated.
METHODS: We undertook a double-blind, randomised, controlled trial of 3,152 patients aged 60 years or older with New York Heart Association class II-IV heart failure and ejection fraction of 40% or less. Patients, stratified for beta-blocker use, were randomly assigned losartan (n=1,578) titrated to 50 mg once daily or captopril (n=1,574) titrated to 50 mg three times daily. The primary and secondary endpoints were all-cause mortality, and sudden death or resuscitated arrest. We assessed safety and tolerability. Analysis was by intention to treat.
FINDINGS: Median follow-up was 555 days. There were no significant differences in all-cause mortality (11.7 vs 10.4% average annual mortality rate) or sudden death or resuscitated arrests (9.0 vs 7.3%) between the two treatment groups (hazard ratios 1.13 [95.7% CI 0.95-1.35], p=0.16 and 1.25 [95% CI 0.98-1.60], p=0.08). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7 vs 14.7%, p<0.001), including cough (0.3 vs 2.7%).
Marc A Pfeffer, John J V McMurray, Eric J Velazquez, Jean-Lucien Rouleau, Lars Køber, Aldo P Maggioni, Scott D Solomon, Karl Swedberg, Frans Van de Werf, Harvey White, Jeffrey D Leimberger, Marc Henis, Susan Edwards, Steven Zelenkofske, Mary Ann Sellers, Robert M Califf, Valsartan in Acute Myocardial Infarction Trial Investigators
Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
N Engl J Med. 2003 Nov 13;349(20):1893-906. doi: 10.1056/NEJMoa032292. Epub 2003 Nov 10.
Abstract/Text
BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. In a double-blind trial, we compared the effect of the angiotensin-receptor blocker valsartan, the ACE inhibitor captopril, and the combination of the two on mortality in this population of patients.
METHODS: Patients receiving conventional therapy were randomly assigned, 0.5 to 10 days after acute myocardial infarction, to additional therapy with valsartan (4909 patients), valsartan plus captopril (4885 patients), or captopril (4909 patients). The primary end point was death from any cause.
RESULTS: During a median follow-up of 24.7 months, 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group (hazard ratio in the valsartan group as compared with the captopril group, 1.00; 97.5 percent confidence interval, 0.90 to 1.11; P=0.98; hazard ratio in the valsartan-and-captopril group as compared with the captopril group, 0.98; 97.5 percent confidence interval, 0.89 to 1.09; P=0.73). The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001). The valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group.
CONCLUSIONS: Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival.
Copyright 2003 Massachusetts Medical Society
Karl Swedberg, Michel Komajda, Michael Böhm, Jeffrey S Borer, Ian Ford, Ariane Dubost-Brama, Guy Lerebours, Luigi Tavazzi, SHIFT Investigators
Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
Lancet. 2010 Sep 11;376(9744):875-85. doi: 10.1016/S0140-6736(10)61198-1.
Abstract/Text
BACKGROUND: Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure.
METHODS: Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7.5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960.
FINDINGS: 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22.9 (IQR 18-28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0.82, 95% CI 0.75-0.90, p<0.0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; HR 0.74, 0.66-0.83; p<0.0001) and deaths due to heart failure (151 [5%] vs 113 [3%]; HR 0.74, 0.58-0.94, p=0.014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0.025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<0.0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<0.0001).
INTERPRETATION: Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder.
FUNDING: Servier, France.
Copyright 2010 Elsevier Ltd. All rights reserved.
Nadia Bouabdallaoui, Eileen O'Meara, Virginie Bernier, Michel Komajda, Karl Swedberg, Luigi Tavazzi, Jeffrey S Borer, Michael Bohm, Ian Ford, Jean-Claude Tardif
Beneficial effects of ivabradine in patients with heart failure, low ejection fraction, and heart rate above 77 b.p.m.
ESC Heart Fail. 2019 Dec;6(6):1199-1207. doi: 10.1002/ehf2.12513. Epub 2019 Oct 8.
Abstract/Text
AIMS: Ivabradine has been approved in heart failure with reduced ejection fraction (HFrEF) and elevated heart rate despite guideline-directed medical therapy (GDMT) to reduce cardiovascular (CV) death and hospitalization for worsening HF. The median value of 77 b.p.m. is the lower bound selected for the regulatory approval in Canada, South Africa, and Australia. Patient-reported outcomes (PROs) including symptoms, quality of life, and global assessment are considered of major interest in the global plan of care of patients with HF. However, the specific impact of GDMT, and specifically ivabradine, on PRO remains poorly studied. In the subgroup of patients from the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) who had heart rate above the median of 77 b.p.m. (pre-specified analysis) and for whom the potential for improvement was expected to be larger, we aimed (i) to evaluate the effects of ivabradine on PRO (symptoms, quality of life, and global assessment); (ii) to consolidate the effects of ivabradine on the primary composite endpoint of CV death and hospitalization for HF; and (iii) to reassess the effects of ivabradine on left ventricular (LV) remodelling.
METHODS AND RESULTS: Comparisons were made according to therapy, and proportional hazards models (adjusted for baseline beta-blocker therapy) were used to estimate the association between ivabradine and various outcomes. In SHIFT, n = 3357 (51.6%) patients had a baseline heart rate > 77 b.p.m. After a median follow-up of 22.9 months (inter-quartile range 18-28 months), ivabradine on top of GDMT improved symptoms (28% vs. 23% improvement in New York Heart Association functional class, P = 0.0003), quality of life (5.3 vs. 2.2 improvement in Kansas City Cardiomyopathy Questionnaire overall summary score, P = 0.005), and global assessment [from both patient (improved in 72.3%) and physician (improved in 61.0%) perspectives] significantly more than did placebo (both P < 0.0001). Ivabradine induced a 25% reduction in the combined endpoint of CV death and hospitalization for HF (hazard ratio 0.75; P < 0.0001), which translates into a number of patients needed to be treated for 1 year of 17. Patients under ivabradine treatment demonstrated a significant reduction in LV dimensions when reassessed at 8 months (P < 0.05).
CONCLUSIONS: In patients with chronic HFrEF, sinus rhythm, and a heart rate > 77 b.p.m. while on GDMT, the present analysis brings novel insights into the role of ivabradine in improving the management of HFrEF, particularly with regard to PRO (ISRCTN70429960).
© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
Hiroyuki Tsutsui, Shin-Ichi Momomura, Akira Yamashina, Hiroaki Shimokawa, Yasuki Kihara, Yoshihiko Saito, Nobuhisa Hagiwara, Hiroshi Ito, Masafumi Yano, Kazuhiro Yamamoto, Junya Ako, Takayuki Inomata, Yasushi Sakata, Takashi Tanaka, Yasushi Kawasaki, J-SHIFT Study Investigators
Efficacy and Safety of Ivabradine in Japanese Patients With Chronic Heart Failure - J-SHIFT Study.
Circ J. 2019 Sep 25;83(10):2049-2060. doi: 10.1253/circj.CJ-19-0227. Epub 2019 Aug 8.
Abstract/Text
BACKGROUND: Increased heart rate (HR) is an independent risk factor for cardiovascular outcomes in chronic heart failure (HF). Ivabradine, anIfinhibitor, improved outcomes in patients with HF and reduced ejection fraction (HFrEF) in the SHIFT study. We evaluated its efficacy and safety in Japanese HFrEF patients in a randomized, double-blind, placebo-controlled phase III study: the J-SHIFT study. The main objective was to confirm a hazard ratio of <1 in the primary composite endpoint of cardiovascular death or hospital admission for worsening HF.Methods and Results:Patients with NYHA functional class II-IV, left ventricular EF ≤35%, and resting HR ≥75 beats/min in sinus rhythm under optimal medical therapy received ivabradine (n=127) or placebo (n=127). Mean reduction in resting HR was significantly greater in the ivabradine group (15.2 vs. 6.1 beats/min, P<0.0001). However, symptomatic bradycardia did not occur. A total of 26 (20.5%) patients in the ivabradine group and 37 (29.1%) patients in the placebo group had the primary endpoint event (hazard ratio 0.67, 95% CI 0.40-1.11, P=0.1179) during median follow-up of 589 days. Mild phosphenes were reported in 8 (6.3%) patients in the ivabradine group and 4 (3.1%) patients in the placebo group (P=0.3760).
CONCLUSIONS: The J-SHIFT study supported the efficacy and safety of ivabradine for Japanese HFrEF patients, in accord with the SHIFT study.
John J V McMurray, Milton Packer, Akshay S Desai, Jianjian Gong, Martin P Lefkowitz, Adel R Rizkala, Jean L Rouleau, Victor C Shi, Scott D Solomon, Karl Swedberg, Michael R Zile, PARADIGM-HF Investigators and Committees
Angiotensin-neprilysin inhibition versus enalapril in heart failure.
N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.
Abstract/Text
BACKGROUND: We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients.
METHODS: In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.
RESULTS: The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.
CONCLUSIONS: LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
Hiroyuki Tsutsui, Shinichi Momomura, Yoshihiko Saito, Hiroshi Ito, Kazuhiro Yamamoto, Tomomi Ohishi, Naoko Okino, Weinong Guo
Efficacy and safety of sacubitril/valsartan (LCZ696) in Japanese patients with chronic heart failure and reduced ejection fraction: Rationale for and design of the randomized, double-blind PARALLEL-HF study.
J Cardiol. 2017 Sep;70(3):225-231. doi: 10.1016/j.jjcc.2016.11.011. Epub 2016 Dec 24.
Abstract/Text
BACKGROUND: The prognosis of heart failure patients with reduced ejection fraction (HFrEF) in Japan remains poor, although there is growing evidence for increasing use of evidence-based pharmacotherapies in Japanese real-world HF registries. Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor shown to reduce mortality and morbidity in the recently completed largest outcome trial in patients with HFrEF (PARADIGM-HF trial). The prospectively designed phase III PARALLEL-HF (Prospective comparison of ARNI with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) study aims to assess the clinical efficacy and safety of LCZ696 in Japanese HFrEF patients, and show similar improvements in clinical outcomes as the PARADIGM-HF study enabling the registration of LCZ696 in Japan.
METHODS AND DESIGN: This is a multicenter, randomized, double-blind, parallel-group, active controlled study of 220 Japanese HFrEF patients. Eligibility criteria include a diagnosis of chronic HF (New York Heart Association Class II-IV) and reduced ejection fraction (left ventricular ejection fraction ≤35%) and increased plasma concentrations of natriuretic peptides [N-terminal pro B-type natriuretic peptide (NT-proBNP) ≥600pg/mL, or NT-proBNP ≥400pg/mL for those who had a hospitalization for HF within the last 12 months] at the screening visit. The study consists of three phases: (i) screening, (ii) single-blind active LCZ696 run-in, and (iii) double-blind randomized treatment. Patients tolerating LCZ696 50mg bid during the treatment run-in are randomized (1:1) to receive LCZ696 100mg bid or enalapril 5mg bid for 4 weeks followed by up-titration to target doses of LCZ696 200mg bid or enalapril 10mg bid in a double-blind manner. The primary outcome is the composite of cardiovascular death or HF hospitalization and the study is an event-driven trial.
CONCLUSIONS: The design of the PARALLEL-HF study is aligned with the PARADIGM-HF study and aims to assess the efficacy and safety of LCZ696 in Japanese HFrEF patients.
Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
John G F Cleland, Jean-Claude Daubert, Erland Erdmann, Nick Freemantle, Daniel Gras, Lukas Kappenberger, Luigi Tavazzi, Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators
The effect of cardiac resynchronization on morbidity and mortality in heart failure.
N Engl J Med. 2005 Apr 14;352(15):1539-49. doi: 10.1056/NEJMoa050496. Epub 2005 Mar 7.
Abstract/Text
BACKGROUND: Cardiac resynchronization reduces symptoms and improves left ventricular function in many patients with heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony. We evaluated its effects on morbidity and mortality.
METHODS: Patients with New York Heart Association class III or IV heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony who were receiving standard pharmacologic therapy were randomly assigned to receive medical therapy alone or with cardiac resynchronization. The primary end point was the time to death from any cause or an unplanned hospitalization for a major cardiovascular event. The principal secondary end point was death from any cause.
RESULTS: A total of 813 patients were enrolled and followed for a mean of 29.4 months. The primary end point was reached by 159 patients in the cardiac-resynchronization group, as compared with 224 patients in the medical-therapy group (39 percent vs. 55 percent; hazard ratio, 0.63; 95 percent confidence interval, 0.51 to 0.77; P<0.001). There were 82 deaths in the cardiac-resynchronization group, as compared with 120 in the medical-therapy group (20 percent vs. 30 percent; hazard ratio 0.64; 95 percent confidence interval, 0.48 to 0.85; P<0.002). As compared with medical therapy, cardiac resynchronization reduced the interventricular mechanical delay, the end-systolic volume index, and the area of the mitral regurgitant jet; increased the left ventricular ejection fraction; and improved symptoms and the quality of life (P<0.01 for all comparisons).
CONCLUSIONS: In patients with heart failure and cardiac dyssynchrony, cardiac resynchronization improves symptoms and the quality of life and reduces complications and the risk of death. These benefits are in addition to those afforded by standard pharmacologic therapy. The implantation of a cardiac-resynchronization device should routinely be considered in such patients.
Copyright 2005 Massachusetts Medical Society.
John G F Cleland, Jean-Claude Daubert, Erland Erdmann, Nick Freemantle, Daniel Gras, Lukas Kappenberger, Luigi Tavazzi, Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators
The effect of cardiac resynchronization on morbidity and mortality in heart failure.
N Engl J Med. 2005 Apr 14;352(15):1539-49. doi: 10.1056/NEJMoa050496. Epub 2005 Mar 7.
Abstract/Text
BACKGROUND: Cardiac resynchronization reduces symptoms and improves left ventricular function in many patients with heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony. We evaluated its effects on morbidity and mortality.
METHODS: Patients with New York Heart Association class III or IV heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony who were receiving standard pharmacologic therapy were randomly assigned to receive medical therapy alone or with cardiac resynchronization. The primary end point was the time to death from any cause or an unplanned hospitalization for a major cardiovascular event. The principal secondary end point was death from any cause.
RESULTS: A total of 813 patients were enrolled and followed for a mean of 29.4 months. The primary end point was reached by 159 patients in the cardiac-resynchronization group, as compared with 224 patients in the medical-therapy group (39 percent vs. 55 percent; hazard ratio, 0.63; 95 percent confidence interval, 0.51 to 0.77; P<0.001). There were 82 deaths in the cardiac-resynchronization group, as compared with 120 in the medical-therapy group (20 percent vs. 30 percent; hazard ratio 0.64; 95 percent confidence interval, 0.48 to 0.85; P<0.002). As compared with medical therapy, cardiac resynchronization reduced the interventricular mechanical delay, the end-systolic volume index, and the area of the mitral regurgitant jet; increased the left ventricular ejection fraction; and improved symptoms and the quality of life (P<0.01 for all comparisons).
CONCLUSIONS: In patients with heart failure and cardiac dyssynchrony, cardiac resynchronization improves symptoms and the quality of life and reduces complications and the risk of death. These benefits are in addition to those afforded by standard pharmacologic therapy. The implantation of a cardiac-resynchronization device should routinely be considered in such patients.
Copyright 2005 Massachusetts Medical Society.
Michael R Bristow, Leslie A Saxon, John Boehmer, Steven Krueger, David A Kass, Teresa De Marco, Peter Carson, Lorenzo DiCarlo, David DeMets, Bill G White, Dale W DeVries, Arthur M Feldman, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators
Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
N Engl J Med. 2004 May 20;350(21):2140-50. doi: 10.1056/NEJMoa032423.
Abstract/Text
BACKGROUND: We tested the hypothesis that prophylactic cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays.
METHODS: A total of 1520 patients who had advanced heart failure (New York Heart Association class III or IV) due to ischemic or nonischemic cardiomyopathies and a QRS interval of at least 120 msec were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers, and spironolactone) alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker-defibrillator. The primary composite end point was the time to death from or hospitalization for any cause.
RESULTS: As compared with optimal pharmacologic therapy alone, cardiac-resynchronization therapy with a pacemaker decreased the risk of the primary end point (hazard ratio, 0.81; P=0.014), as did cardiac-resynchronization therapy with a pacemaker-defibrillator (hazard ratio, 0.80; P=0.01). The risk of the combined end point of death from or hospitalization for heart failure was reduced by 34 percent in the pacemaker group (P<0.002) and by 40 percent in the pacemaker-defibrillator group (P<0.001 for the comparison with the pharmacologic-therapy group). A pacemaker reduced the risk of the secondary end point of death from any cause by 24 percent (P=0.059), and a pacemaker-defibrillator reduced the risk by 36 percent (P=0.003).
CONCLUSIONS: In patients with advanced heart failure and a prolonged QRS interval, cardiac-resynchronization therapy decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.
Copyright 2004 Massachusetts Medical Society
Michael R Bristow, Leslie A Saxon, John Boehmer, Steven Krueger, David A Kass, Teresa De Marco, Peter Carson, Lorenzo DiCarlo, David DeMets, Bill G White, Dale W DeVries, Arthur M Feldman, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators
Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
N Engl J Med. 2004 May 20;350(21):2140-50. doi: 10.1056/NEJMoa032423.
Abstract/Text
BACKGROUND: We tested the hypothesis that prophylactic cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays.
METHODS: A total of 1520 patients who had advanced heart failure (New York Heart Association class III or IV) due to ischemic or nonischemic cardiomyopathies and a QRS interval of at least 120 msec were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers, and spironolactone) alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker-defibrillator. The primary composite end point was the time to death from or hospitalization for any cause.
RESULTS: As compared with optimal pharmacologic therapy alone, cardiac-resynchronization therapy with a pacemaker decreased the risk of the primary end point (hazard ratio, 0.81; P=0.014), as did cardiac-resynchronization therapy with a pacemaker-defibrillator (hazard ratio, 0.80; P=0.01). The risk of the combined end point of death from or hospitalization for heart failure was reduced by 34 percent in the pacemaker group (P<0.002) and by 40 percent in the pacemaker-defibrillator group (P<0.001 for the comparison with the pharmacologic-therapy group). A pacemaker reduced the risk of the secondary end point of death from any cause by 24 percent (P=0.059), and a pacemaker-defibrillator reduced the risk by 36 percent (P=0.003).
CONCLUSIONS: In patients with advanced heart failure and a prolonged QRS interval, cardiac-resynchronization therapy decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.
Copyright 2004 Massachusetts Medical Society
