CLINICAL RESEARCH: HEART FAILURE
Continental Differences in Clinical Characteristics, Management, and Outcomes in Patients Hospitalized With Worsening Heart FailureResults From the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) Program
John E.A. Blair, MD*,
Faiez Zannad, MD ,
Marvin A. Konstam, MD, FACC ,
Thomas Cook, PhD ,
Brian Traver, MS,
John C. Burnett, Jr, MD||,
Liliana Grinfeld, MD, FACC¶,
Holly Krasa, MS#,
Aldo P. Maggioni, MD**,
Cesare Orlandi, MD, FACC#,
Karl Swedberg, MD, PhD, FACC,
James E. Udelson, MD, FACC,
Christopher Zimmer, MD#,
Mihai Gheorghiade, MD, FACC*,* for the EVEREST Investigators
* Northwestern University Feinberg School of Medicine, Chicago, Illinois
Institut National de la Santé et de la Recherche Médicale (INSERM), Nancy, France
Tufts-New England Medical Center, Boston, Massachusetts
University of Wisconsin, Madison, Wisconsin
|| Mayo Clinic, Rochester, Minnesota
¶ Hospital Italiano, Buenos Aires, Argentina
# Otsuka Maryland Research Institute, Rockville, Maryland
** Associazione Nazionale Medici Cardioligi Ospedalieri Research Center, Florence, Italy
Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
Manuscript received April 15, 2008;
revised manuscript received June 27, 2008,
accepted July 10, 2008.
* Reprint requests and correspondence: Dr. Mihai Gheorghiade, Northwestern University, Feinberg School of Medicine, 201 East Huron Street, Galter 10-240, Chicago, Illinois 60611 (Email: m-gheorghiade{at}northwestern.edu).
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Abstract
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Objectives: Our aim was to examine continental and regional differences in baseline characteristics and post-discharge clinical outcomes in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial.
Background: Continental and regional differences in clinical trials of acute heart failure syndromes (AHFS) have not been well studied.
Methods: We analyzed data from the EVEREST trial, which randomized 4,133 patients hospitalized for worsening (HF) and left ventricular ejection fraction  40% to oral tolvaptan, a vasopressin antagonist, or placebo and followed for a median of 9.9 months. Baseline characteristics, mortality, and outcomes were analyzed across North America (n = 1,251), South America (n = 688), Western Europe (564 patients), and Eastern Europe (n = 1,619).
Results: There were major differences between the 4 groups in the severity, etiology, and management of HF. Unadjusted 1-year mortality and cardiovascular mortality/HF hospitalization were 30.4% and 52.5% in North America, 27.2% and 41.6% in South America, 27.1% and 47.3% in Western Europe, and 20.5% and 35.3% in Eastern Europe. After adjustment, South American patients had the highest overall mortality (hazard ratio: 1.42, 95% confidence interval: 1.15 to 1.76), while Eastern European patients had the lowest cardiovascular death and HF hospitalization rate (hazard ratio: 0.84, 95% confidence interval: 0.73 to 0.97), compared with patients in North America.
Conclusions: Major continental and regional differences in HF severity, etiology, and management exist among AHFS patients, resulting in varied post-discharge outcomes, despite pre-defined selection criteria. These differences should be taken into account when planning global trials in AHFS. (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan [EVEREST]; NCT00071331)
Key Words: heart failure • regional differences • outcomes
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Abbreviations and Acronyms
| | AHFS = acute heart failure syndromes | | BNP = B-type natriuretic peptide | | CI = confidence interval | | CV = cardiovascular | | HF = heart failure | | HR = hazard ratio | | ICD = implantable cardioverter-defibrillator |
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Heart failure (HF) is a major public health problem internationally. In the U.S. alone, >5 million individuals are affected, with 550,000 new cases yearly, >1 million hospitalizations in 2004, and an approximated $33 billion in health care costs in 2007 (1). Similar epidemiology and public health burden has been reported in Europe (2), and the incidence of HF is rising in developing countries (3). Despite advances in medical therapy for chronic HF, the number of admissions for acute heart failure syndromes (AHFS) continues to rise, and mortality for these patients remains high. Hospitalization for AHFS is one of the most important predictors of morbidity and mortality in the chronic HF population (4,5). In-hospital mortality rates are 4% to 7% while 60- to 90-day mortality and readmission rates are 7% to 9% and 24% to 30%, respectively (6).
As AHFS patients constitute a heterogeneous group, variations in patient characteristics may play a role in the clinical outcome of these patients. Contemporary registries demonstrate important differences between continents and regions within continents in HF etiology, HF severity, and management of HF (7–13). As a result, cardiovascular (CV) outcomes vary between these continents. However, in a randomized trial, due to pre-specified inclusion and exclusion criteria, it is expected that these differences are less likely to occur and may not influence the overall outcome of a trial. The EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program demonstrated that the oral vasopressin antagonist, tolvaptan, added to standard therapy, improved some, but not all, HF signs and symptoms during hospitalization over placebo; it showed no effect on long-term mortality or HF-related morbidity (14,15). This large trial, which enrolled patients from 3 continents and 2 regions in Europe, provides a unique opportunity to look at these continental and regional differences.
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Methods
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Patients.
The design of the EVEREST program has been described previously (16). This prospective, international, randomized, double-blind, placebo-controlled program examined the short- and long-term efficacy and safety of tolvaptan added to optimal medical therapy in patients hospitalized for worsening HF. There were 2 identical short-term trials during the inpatient period (trials A and B), embedded in a long-term post-discharge outcome study combining all patients.
Adults  18 years of age with left ventricular ejection fraction 40%, hospitalized primarily for worsening of HF and with 2 or more signs of fluid overload, were randomized within 48 h of hospitalization to oral tolvaptan (30 mg/day) or matching placebo in addition to conventional therapy. Exclusion criteria were cardiac surgery within 60 days of enrollment, cardiac mechanical support, biventricular pacemaker placement within 60 days, expected survival of <6 months, acute myocardial infarction at the time of hospitalization, hemodynamically significant uncorrected primary cardiac valvular disease, end-stage HF, dialysis, systolic blood pressure <90 mm Hg, serum creatinine more than 3.5 mg/dl, serum potassium more than 5.5 mEq/l, and hemoglobin <9 g/dl. Background therapy was at the discretion of the treating physician, but specific recommendations for guideline-based optimal medical therapy were included in the study protocol. For administrative reasons, B-type natriuretic peptide (BNP) collection was incomplete, and we report on the available samples from each center. Furthermore, the distribution of BNP measurements was highly skewed, so we summarized BNP using the medians and interquartile ranges. For analysis of QRS duration, this interval was not reported in 142 patients, and 1,029 patients were excluded due to the presence of a pacemaker and/or implantable cardioverter-defibrillator (ICD).
In all, 4,133 patients were randomized in 359 sites in 20 countries in the 3 continents of North America, South America, and Europe between October 7, 2003, and February 3, 2006, with follow-up until July 6, 2006. For this analysis, Europe was divided into the regions of Eastern Europe and Western Europe. The countries were grouped as follows: North America: U.S. and Canada; South America: Argentina and Brazil; Western Europe: Italy, Belgium, Norway, Netherlands, Germany, Spain, France, United Kingdom, Sweden, and Switzerland; and Eastern Europe: Poland, Romania, Czech Republic, Russia, Bulgaria, and Lithuania.
End point assessment.
The short-term primary end point was a composite score of changes in patient-assessed global clinical status based on a visual analog scale and body weight measured post-void on a standardized scale from baseline to day 7 or discharge if earlier. Long-term primary end points were all-cause mortality and the composite of CV death or hospitalization for HF. The median follow-up period was 9.9 months. The mode of death and CV hospitalizations were adjudicated by an independent event committee for all patients during the follow-up period.
Statistical analysis.
Post-hoc analyses were performed on the entire randomized population, with patients grouped based on continent of enrollment or region within Europe. Demographics, physical and laboratory findings, medical history, and medical, revascularization, and device therapies were simultaneously compared among the 4 groups using the Kruskal-Wallis test for continuous variables and the Pearson chi-square test for categorical variables. Unadjusted Kaplan-Meier estimates of the rates of all-cause mortality and CV death/HF hospitalization were calculated at 3 months and 1 year. Hazard ratios (HRs) and corresponding confidence intervals (CIs) for mortality and the composite end point were calculated relative to North America at 3 months and over the entire follow-up period (9.9 months median follow-up) using a Cox proportional hazards model with and without adjustment for other baseline covariates. Baseline variables reaching a significance level of p < 0.05 were retained.
The sponsor performed database management according to a pre-specified plan, and the University of Wisconsin Statistical Data Analysis Center conducted all final analyses using SAS software, version 8.2 (SAS Institute Inc., Cary, North Carolina) and R software (R Development Core Team, R Foundation for Statistical Computing, Vienna, Austria). The authors had full access to the data and take responsibility for its integrity.
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Results
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Of the 4,133 patients enrolled in 359 sites, there were 1,251 (30.3%) patients, 173 (48.2%) sites, and 7.2 patients per site in North America, 699 (16.9%) patients, 35 sites (9.7%), and 20.0 patients per site in South America, 564 (13.6%) patients, 77 (21.4%) sites, and 8.1 patients per site in Western Europe, and 1,619 (39.2%) patients, 74 (20.6%) sites, and 20.0 patients per site in Eastern Europe.
There were several differences between continents and regions (Table 1). The major differences are outlined in the following text.
Physical and laboratory findings.
Patients in Eastern Europe had the highest systolic blood pressure (125.9 mm Hg compared with 116.6, 117.4, and 117.4 mm Hg in North America, South America, and Western Europe, respectively) and left ventricular ejection fraction (30.5% compared with 24.6%, 26.0%, and 27.2% in North America, South America, and Western Europe, respectively), and the lowest serum blood urea nitrogen (25.7 mg/dl compared with 35.1, 28.3, and 35.1 mg/dl in North America, South America, and Western Europe, respectively) and BNP (533 pg/ml compared with 1,031, 694, and 720 mg/dl in North America, South America, and Western Europe, respectively).
Medical history.
Patients in South America had the lowest rates of coronary artery disease (39.9% compared with 77.4%, 64.0%, and 80.5% in North America, Western Europe, and Eastern Europe, respectively) and previous myocardial infarction (29.5% compared with 55.5%, 48.8%, and 56.3% in North America, Western Europe, and Eastern Europe, respectively). Patients in Eastern Europe had the highest rate of atrial fibrillation on admission (36.0% compared with 15.5%, 23.5%, and 30.1% in North America, South America, and Western Europe, respectively), and patients in North America had the highest rates of comorbidities, including hypertension, hypercholesterolemia, diabetes, chronic kidney disease, severe obstructive lung disease, and peripheral vascular disease.
Revascularization and device use.
The use of percutaneous and surgical revascularization was highest in North America (32.6% and 41.4%) and Western Europe (24.5% and 24.5%) and lowest in South America (12.3% and 13.3%) and Eastern Europe (6.6% and 7.0%). A similar pattern was found for pacemaker use. The use of ICDs was the highest in North America (34.2% compared with 2.7%, 12.6%, and 5.1% in South America, Western Europe, and Eastern Europe, respectively).
Medication use.
Most patients were on diuretic therapy at randomization and at discharge (Table 2). There was greater beta-blocker use in North America and Eastern Europe, greater use of nitroglycerin and lipid-lowering agents in North America and Western Europe, greater use of spironolactone in South America and Eastern Europe, and equal use of digoxin across all regions except for Western Europe. Inotropic agent use was highest in North America (7.6% at randomization compared with 3.4%, 5.7%, and 1.0% in South America, Western Europe, and Eastern Europe, respectively). Most patients were off inotropic agents and intravenous nitroglycerin by discharge, except for a small percentage of patients (4.1%) in North America still on inotropic agents. As seen in Table 2, the addition of medications known to improve long-term outcomes in patients with HF such as angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and spironolactone occurred infrequently during hospitalization and did not substantially differ across regions.
Outcomes.
Unadjusted 1-year Kaplan-Meier estimates of mortality were highest in North America (30.4%), followed by South America (27.2%), Western Europe (27.1%), and Eastern Europe (20.5%) (Table 3, Fig. 1). Compared with North America, the overall unadjusted risk of death was similar in South America and Western Europe, but was significantly lower in Eastern Europe (HR: 0.63, 95% CI: 0.54 to 0.73) (Table 4). After adjusting for important baseline characteristics, the overall risk of death was similar in Western Europe and Eastern Europe, but elevated in patients from South America (HR: 1.58, 95% CI: 1.11 to 2.25 at 3 months; HR: 1.42, 95% CI: 1.15 to 1.76 overall) compared with that in North America.
Unadjusted 1-year Kaplan-Meier estimates of CV death or HF hospitalization were highest in North America (52.5%), followed by Western Europe (47.3%), South America (41.6%), and Eastern Europe (35.3%) (Table 3, Fig. 2). Compared with North America, the overall unadjusted risk for CV death or HF hospitalization was similar in Western Europe, but lower in South America and Eastern Europe. After adjusting for baseline variables, Eastern Europe was the only region with lower overall CV death or HF hospitalization rates (HR: 0.84, 95% CI: 0.73 to 0.97) compared with North America (Table 4).
After adjudication of all events in the study, the main cause of death was HF in North America, South America, and Western Europe (42.9%, 44.0%, and 47.9%, respectively), whereas it was sudden cardiac death in Eastern Europe (35.5%) (Table 5). The main reason for rehospitalization was HF in all continents.
Early treatment termination at 1 year was most common in North America (33.7%), followed by Western Europe (24.3%), Eastern Europe (14.2%), and South America (13.5%), and did not differ based on active medication.
The 2 components of the short-term primary end point were weight loss and change in baseline global status from randomization to day 7 or discharge if sooner. It appeared that there was a significant difference between continents and regions in weight loss (p = 0.022), but not in global status (Figs. 3 and 4) when comparing the tolvaptan groups to placebo groups. In terms of the long-term primary end points, the addition of tolvaptan to standard therapy did not appear to affect post-discharge or the combined end point of CV mortality and HF hospitalization in any of the 4 regions (15).
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Discussion
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This study demonstrates significant differences in HF severity, etiology, and management among different continents and regions in a large, international trial in AHFS.
Differences in HF severity.
Several variables have been identified that are important predictors of prognosis in AHFS and in chronic HF. Of the variables measured in the EVEREST program, low systolic blood pressure and serum sodium, and high BNP, blood urea nitrogen, and creatinine are independent predictors of adverse outcomes in AHFS and chronic HF (9,17–23). The Eastern European population had the highest systolic blood pressure and ejection fraction and the lowest blood urea nitrogen and BNP compared with the populations of other regions, placing them at lower risk for death and HF hospitalization.
Differences in HF etiology.
Patients from South America had the lowest rates of coronary artery disease, previous myocardial infarction, and hypercholesterolemia. Other comorbidities, such as diabetes and peripheral vascular disease, were the lowest in South America compared with other continents and regions. The low rates of coronary artery disease as well as other comorbidities were similar in registry data obtained from Argentina (12). In addition, patients in these registries had high rates of hypertensive and valvular HF (23.7% and 20.7%), with a noticeable but low rate of Chagas HF (1.3%), suggesting that the underlying disease process in South America is different than in other continents.
Differences in HF management.
Despite similarities in HF guidelines in the U.S. and Europe, there were important differences in medications, revascularization procedures, and device use between continents and regions (24,25). For example, use of lipid-lowering agents was most frequent in North America and Western Europe, whereas use of spironolactone was most frequent in South America and Eastern Europe. Diuretic and digoxin use was numerically similar across continents and regions. The reasons for this variation have been analyzed in prior studies and may depend on multiple factors ranging from patient characteristics to the reimbursement structure of the particular country (26,27). There was also a difference in beta-blocker use, with a 22% lower rate of use in South America than in North America. Revascularization, pacemaker, and ICD use was highest in North America and Western Europe and lowest in South America and Eastern Europe.
Differences in outcomes.
The differences in HF severity, etiology, and treatment were associated with differences in outcome in the EVEREST trial. The Eastern European population, for example, had the best overall unadjusted short- and long-term outcomes compared with the other continents or regions, likely due to the low severity of HF at randomization in this trial. After adjustment for major covariates, this difference in outcomes disappeared, stressing the importance of these variables on outcome.
Implications.
This analysis has implications in the design of future AHFS trials. The main inclusion criterion for AHFS trials is based on the perceived need for hospital admission. Since this may be influenced by differences in local medical practice as well as by differences in health care systems, using objective measurements of severity (e.g., BNP levels) may help enroll a more homogenous group of patients. In addition, a drug effect may be observed in relation to the etiology predominant to a particular region. For example, in the OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbation of Chronic Heart Failure) study, the short-term use of milrinone was deleterious and was associated with a significant increase in post-discharge mortality only in patients with coronary artery disease (28). Finally, the effects of a particular investigational drug may be affected by background HF therapies. For example, it is possible that interventions targeted to sudden cardiac death or progression of HF may not improve outcomes in patients already treated with ICDs or cardiac resynchronization therapy, the use of which varied dramatically between continents and regions.
Study limitations.
Our analysis was performed on data rigorously collected in the setting of a clinical trial, with every patient chosen based on pre-specified strict selection criteria, and may not represent the true severity, etiology, and management in a given region. Registries of consecutive patients may better identify differences between regions. Nevertheless, knowing differences between regions in a large clinical trial is important for trial design. In addition, this was a subgroup analysis. Although adjusted analysis has been performed considering the possible confounding factors, differences could be due to chance, and potential confounders may not have been identified.
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Conclusions
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These data demonstrated that despite efforts to select for a fairly homogenous study population, important differences in etiology, severity, management, and outcomes existed. The etiology and management of HF may vary by region and is difficult to control. Future AHFS trials should take these continental and regional differences into consideration and possibly stratify randomization based on continent or region when appropriate and analyze the data separately.
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Footnotes
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The EVEREST program was funded by Otsuka. Drs. Zannad, Konstam, Burnett, Grinfeld, Maggioni, Swedberg, Udelson, and Gheorghiade report receiving funding from Otsuka. Drs. Zimmer, Orlandi, and Ms. Krasa have been or are employees of Otsuka. Dr. Cook and Mr. Traver received compensation through a contract between the University of Wisconsin and Otsuka Pharmaceutical Development & Commercialization, Inc.
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References
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Abstract
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