Elsevier

American Heart Journal

Volume 159, Issue 5, May 2010, Pages 841-849.e1
American Heart Journal

Clinical Investigation
Congestive Heart Failure
Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: Results from efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) program

https://doi.org/10.1016/j.ahj.2010.02.023Get rights and content

Background

The postdischarge rehospitalization and death rates are high in patients with acute heart failure (HF) syndromes despite optimization of standard therapy for chronic HF. To the best of our knowledge, there has been no systematic analysis of the causes of death and rehospitalization in this patient population.

Methods

This was a prespecified analysis of adjudicated cause-specific all-cause mortality and cardiovascular (CV) hospitalization in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, a randomized, double-blind, placebo-controlled study in patients hospitalized with worsening HF and left ventricular ejection fraction ≤40% comparing tolvaptan, an oral vasopressin receptor antagonist to placebo, in addition to standard care.

Results

Of the 4,133 randomized, there were 5,239 rehospitalizations and 1,080 deaths during a median of 9.9 months. Of all deaths, 41.0% were due to HF, 26.0% due to sudden cardiac death (SCD), 2.6% due to acute myocardial infarction (MI), 2.2% due to stroke, and 13.2% due to non-CV causes. Of all hospitalizations, 39.2% were non-CV, whereas 46.3% were for HF, and a minority of hospitalizations was due to stroke, MI, arrhythmia, or other CV causes.

Conclusions

Despite close follow-up and evidence-based therapy within a clinical trial, rehospitalization and death remain high. Although most deaths were from HF, one quarter of patients had SCD. In addition, there were almost as many non-CV hospitalizations as HF hospitalizations. Knowledge of the causes of death and rehospitalization may be essential for proper management and early initiation of therapy.

Section snippets

Study design and population

The design and results of the EVEREST program has been reported previously.14, 15, 16 The trial was an event-driven, randomized, double-blind, placebo-controlled study designed to evaluate both the short-term and long-term efficacy of tolvaptan (an oral vasopressin V2 receptor blocker) supplemented to standard HF therapy in patients hospitalized with worsened HF. This patient population was enrolled at 359 sites and 20 countries throughout North America, Europe, and South America between

Study population

Of the 4,133 patients randomized in the EVEREST trial observed for a median of 9.9 months, there were 5,239 rehospitalizations and 1,080 deaths. As previously reported, there were no differences in the primary end points between the tolvaptan and placebo groups, and the Kaplan-Meier estimated 1-year mortality rate was 25.5%, and the hospitalization rate was 57.6%.16

Mode of death

Most deaths were CV deaths (86.8% of all deaths). The leading mode of death was for HF (47.2%), followed by SCD (30.0%), non-CV

Discussion

To the best of our knowledge, this is the first study to systematically and prospectively analyze the cause of death and rehospitalization in a population of patients hospitalized for HF and on modern medical therapy. We demonstrated a high rate of both death and rehospitalization. In addition, we found that most patients died of progressive HF and approximately one quarter of sudden and unexpected death. Despite a clinical trial population with relatively few comorbidities, approximately one

Conclusion

Future registries for AHFS should adjudicate events to obtain a more accurate real-world causes of death and rehospitalization. Eventually, clinical trials should be designed to target specific modes of death and rehospitalization to reduce such events. Knowledge of the causes of these events may allow for early initiation of appropriate treatment strategies in the early postdischarge period after a hospitalization for worsened HF.

Disclosures

Dr O'Connor reports having received funding from the National Heart Lung and Blood Institute (NHLBI), Amgen, Astra, Bristol-Meyers Squibb, GlaxoSmithKline, Guidant, Medtronic, Merck, Nitrox LLC, Novartis, Otsuka, Pfizer, ArcaBioPharma, Sanofi-Sythelabo, and MedPace; Dr Miller Reports having received research grants from Otsuka and Pfizer and honoraria from Medtronic, Nitromed, Novartis, Pfizer, Sanofi, and Scios Inc; Dr Blair reports having been a consultant for SigmaTau; Dr Konstam reports the

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