The death rate among hospitalized heart failure patients with normal and depressed left ventricular ejection fraction in the year following discharge: evolution over a 10-year period

Lilian Grigorian Shamagian, Jose Ramon Gonzalez-Juanatey*, Alfonso Varela Roman, Jose Maria Garcia Acuña and Alejandro Virgós Lamela

Servicio de Cardiologia y Unidad Coronaria, Hospital Clinico Universitario de Santiago, Travesia Choupana s/n, 15706 Santiago de Compostela, Spain

Received 3 January 2005; revised 19 May 2005; accepted 26 May 2005; online publish-ahead-of-print 28 June 2005.

* Corresponding author. Tel: +34 981 950757; fax: +34 981 950985. E-mail address: jose.ramon.gonzalez.juanatey{at}sergas.es


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Aims To investigate whether changes in clinical characteristics and treatment strategies between 1991 and 2001 have had an impact on the survival of patients hospitalized with congestive heart failure (CHF) and whether those with normal left ventricular ejection fraction (LVEF≥50%) differ in this respect from those with depressed LVEF.

Methods and results We studied 1482 patients who had been admitted to the Cardiology Service of a tertiary Spanish hospital in the last 10 years with CHF. Among the 1110 for whom LVEF was evaluated, the prevalence of normal LVEF rose from 37% in the period 1991–96 (Period 1) to 47% in the period 2000–2001 (Period 3). The intensity of both diagnostic and therapeutic measures also increased during this 10-year period. The 1-year survival rate remained virtually unchanged in the whole group of patients, being 82, 84, and 82% in Periods 1, 2 (1997–99), and 3, respectively, even though the prognosis of patients with depressed LVEF (<50%) improved significantly, with 1-year survival rates of 76, 77, and 84% in Periods 1, 2, and 3, respectively; the normal LVEF group had decreasing 1-year survival rates of 88, 86, and 81% in Periods 1, 2, and 3, respectively, although the increased risk of death was not statistically significant.

Conclusion Although in our centre the death rate among hospitalized CHF patients with depressed LVEF during the first year after discharge has tended to fall over the past 10 years, application of current clinical guidelines has led to no such decrease for patients with normal LVEF. This situation points to a need to reconsider the diagnostic and therapeutic strategy to be employed with this latter group of patients.

Key Words: Heart failure • Left ventricular systolic function • Evolution of the prognosis


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
In western countries, some 16 million patients suffer from congestive heart failure (CHF), which has an annual incidence of 1%. The annual death rate among CHF patients is high: the rates of <10% reported in recent clinical trials1,2 are not matched by the rates of up to almost 50% that have been observed in some community studies during the first year of follow-up,35 the discrepancy being attributable not only to the presumably superior treatment and supervision of clinical trial patients but also to the greater age and other disadvantages, such as comorbidity, of patients seen in everyday practice. It is nevertheless undeniable that there have been therapeutic advances over the past 25 years, and in recent studies, a progressive fall in the death rate has been observed among male and female CHF patients of all ages.4,610 However, these studies have not distinguished between patients with depressed left ventricular ejection fraction (LVEF) and patients in whom LVEF is normal, and the clinical trials that have shown the survival of CHF patients to be prolonged by angiotensin-converting enzyme inhibitors (ACE-Is), beta-blockers, aldosterone receptor blockers, and angiotensin receptor blockers (ARBs) have all concentrated on patients with depressed LVEF.1,2,1117 We know of no reports on the evolution of the death rate among patients with normal LVEF, who currently make up between 30 and 50% of all CHF patients.18,19

Here, we report the evolution, over a 10-year period, of the death rate among hospitalized CHF patients in the year following discharge, distinguishing between those with normal and depressed LVEF.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Study groups
We included in the study the 1482 patients who had been admitted to the Cardiology Service of our tertiary hospital between 1 January 1991 and 31 December 2001 complying with the following modified Framingham criteria for CHF: satisfaction of two or more major criteria (paroxysmal nocturnal dyspnoea, orthopnoea, rales, jugular venous distension, third sound, and radiological signs of pulmonary congestion and/or cardiomegaly) or one major criterion together with two or more minor criteria (effort dyspnoea, peripheral oedema, hepatomegaly, and pleural effusion). The great majority of these patients were referred by the Emergency Department; most of the others were admitted via the Cardiology Service outpatient's section. Of the 1482, 1110 had their LVEF measured echocardiographically by the modified Simpson method while they were hospitalized. In the case of patients admitted for CHF on more than one occasion, only the data corresponding to the first admission involving measurement of LVEF were included in the analysis.

The 1482 patients were divided into three groups according to date of admission: those admitted between 1 January 1991 and 31 December 1996 (Period 1; 612 patients); those admitted between 1 January 1997 and 31 December 1999 (Period 2; 417 patients); and those admitted between 1 January 2000 and 31 December 2001 (Period 3; 453 patients). These periods were chosen to make the dates separating them roughly coincide with the publication of major clinical trials leading to changes in clinical guidelines (and hence, in particular, to changes in the frequency with which drugs shown to favour the survival of CHF patients were prescribed in our cardiology service), while at the same time ensuring that the sizes of the three groups (and, in particular, the sizes of the subgroups with LVEF measurements) would not be too dissimilar. Note that the length of the periods decreases progressively partly because of an increasing annual rate of admissions for CHF and partly because of increasing use of echocardiography for evaluation of CHF patients in our service.

Within each group of patients, as defined earlier by the date of admission, the subgroup consisting of patients with LVEF measurements was in turn divided into two groups according to whether LVEF was normal (LVEF ≥50%) or depressed (LVEF <50%).

Data collected
Apart from standard descriptive data (age, sex, etc.), data were collected on the underlying cardiopathy (ischaemic cardiopathy, valve disease, dilated cardiomyopathy, or others); cardiovascular risk factors; clinical signs and symptoms; the results of supplementary tests; the duration of hospitalization; drugs prescribed upon release; and survival during the remainder of the year of admission and the following year (a period defined so as to afford an average maximum possible follow-up time of roughly 1.5 years). The survival information was collected in April–May 2003 by examining the hospital archives and, for patients for whom the archives failed to resolve the question, by telephone survey. Reliable survival data were collected for 86% of the patients. The likely causes of loss to follow-up include their being treated in other centres instead of ours, following the episode that led to their inclusion in the study, and changes of telephone number. This group showed no significant differences from the remainder, whose survival or date of death could be determined in these ways. Patients' flow chart is represented in Figure 1.



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Figure 1 Patients' flow chart.

 
Statistical analysis
Data for categorical or dichotomous variables are presented as per cents and were compared using a {chi}2 test or Fisher's exact test. Data for continuous variables are presented as mean±standard deviations and were compared by analysis of variance. Survival curves were estimated by the Kaplan–Meier method and were compared using log rank tests. Three independent contrasts were performed to compare the survival curves in the whole group and in subgroups with normal and reduced systolic function: (i) overall test comparing three time periods, survival curves; (ii) comparison of the survival curves of Periods 1 and 2; (iii) comparison of the survival curves of Periods 1 and 3. Three independent P-values were obtained for each one of these analyses. Factors with independent significant association with survival were identified (and the possibility of significant date-related factors excluded) using Cox's proportional hazards model, in which the periods were used together with all the clinical and management variables for which there were significant differences in prevalence between Periods 1, 2, and 3 in the present study and those which have been reported to affect survival in previous studies [age, hyperlipidaemia, arterial hypertension, NYHA functional class, third sound, jugular vein distension, cardiomegaly, rales, atrial fibrillation, LVEF (the last one, only in the whole group analysis), ACE-Is and/or ARB, beta-blockers, spironolactone, anticoagulants, digoxin, and calcium channel blockers]. Although sex has not suffered any changes in its prevalence during study periods, it was used to adjust all multivariable analysis. The resulting regression coefficients were used to estimate relative risks and the corresponding 95% confidence intervals (CIs). For each of the subsamples with normal and depressed systolic function, two multivariable analyses similar to that described earlier were performed, in one of which the independent variables were clinical and in the other therapeutic (the last ones adjusted also for age and sex). The validity of the assumption of proportional hazards was supported by the results of calculating log–log survival plots for each variable with age and sex controlled. All comparisons between groups were made using two-sided tests with P<0.05 as the criterion for statistical significance.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Evolution of the clinical characteristics and survival of CHF patients as a group
The statistically significant trends in the characteristics of patients admitted for CHF during the study period were a decrease in the prevalence of some of the major clinical criteria of CHF (third sound, jugular vein distension, alveolar oedema, cardiomegaly), together with an increase in age and in the prevalence of another major risk factor, arterial hypertension. The prevalence of rales, NYHA class IV, and hyperlipidaemia fluctuated widely, with values in Periods 1, 2, and 3 of, respectively, 71, 78, and 74% for rales; 43, 32, and 41% for NYHA class IV; and 29, 23, and 43% for hyperlipidaemia. Among the 1110 patients for whom LVEF was evaluated, the prevalence of normal LVEF rose from 37% in Period 1 to 47% in Period 3.

The intensity of both diagnostic and therapeutic measures also increased: the percentage of patients who underwent echocardiography rose from 74 to 89%, the per cent who underwent coronary angiography rose from 30 to 40%, and there was a rise in the prescription of all drug classes except diuretics, antiaggregants, nitrates, and digoxin (prescription of this last fell from 43 to 21%). All clinical and management characteristics are summarized in Table 1.


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Table 1 Evolution of clinical and management characteristics of hospitalized patients with CHF between 1991 and 2001
 
Survival data were available for 1281 patients (86.4%), 292 of whom (22.8%) had died by the end of the follow-up period (median follow-up time: 1.4 years, interquartile range: 1.1–1.7 years). The 1-year survival rate remained practically unchanged, being 81.9% in Period 1, 84.0% in Period 2, and 82.0% in Period 3 (Figure 2), and multivariable analysis confirmed that risk of death was not significantly influenced by the period in which admission had occurred except via the evolution of other variables (age at admission, hyperlipidaemia, and prescription of ACE-Is, ARBs, and digoxin) (Figure 3).



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Figure 2 Kaplan–Meier survival curves for CHF patients followed up for up to 2 years after discharge during 1991–96 (bold continuous curve), 1997–99 (dotted curve), and 2000–2001 (light continuous curve). RR, relative risk.

 


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Figure 3 Study periods in the whole group of patients adjusted by all the clinical and management variables for which in this study there were significant differences in prevalence between Periods 1, 2, and 3 (see Statistical analysis section) and sex (multivariable Cox analysis). Only variables with P<0.05 and the period are represented. RR, relative risk.

 
Evolution of the clinical characteristics and survival of CHF patients with depressed LVEF
LVEF was <50% in 668 of the 1110 patients for whom it was evaluated. Of these 668, 255 were admitted in Period 1, 205 in Period 2, and 208 in Period 3. In comparison with the group of all CHF patients, in this group, reductions in the prevalence of major clinical criteria of CHF were somewhat less pronounced in the cases of jugular vein distension and alveolar oedema, and somewhat more pronounced in the case of third sound, whereas in the case of cardiomegaly, a coherent trend over the three periods was replaced by a large fluctuation (Table 1). The only systematic downward trend that was statistically significant in this smaller group was that of third sound. In addition, there was again an overall rise in the prevalence of the risk factors hypertension and hyperlipidaemia. At the same time, prescription of ACE-Is, beta-blockers, and spironolactone increased steadily between Periods 1 and 3, whereas prescription of anticoagulants peaked in Period 2 (probably because of a similar peak in atrial fibrillation). As in the whole group, prescription of digoxin was roughly halved.

After the first couple of months, the risk of death within the follow-up period for patients with depressed LVEF fell steadily during the study period (Figure 4, right-hand panel), with 1-year survival rates of 76.0, 78.6, and 83.7% in Periods 1, 2, and 3, respectively. For these patients, the multivariable analyses identified age (which remained unchanged during the study), atrial fibrillation, and third sound (which decreased in prevalence) as increasing the risk of death independently of other clinical variables (Figure 5A); and similarly identified, among the diagnostic and therapeutic variables, prescription of ACE-Is or ARBs and of anticoagulants (all of which increased during the study) as associated with improved survival, and prescription of digoxin (which decreased) as associated with worse survival (Figure 5B). The multivariable analyses confirmed that risk of death was not significantly influenced by the period in which admission had occurred except via the evolution of management. However, changes in clinical variables did not significantly affect the improvement of the prognosis in this group of patients.



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Figure 4 Kaplan–Meier survival curves for CHF patients with normal and depressed LVEF (left and right panels, respectively) followed up for up to 2 years after discharge during 1991–96 (bold continuous curve), 1997–99 (dotted curve), and 2000–2001 (light continuous curve). RR, relative risk.

 


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Figure 5 (A) Study periods in the group of patients with depressed LVEF adjusted by all the clinical variables for which in this study and subgroup there were significant differences in prevalence between Periods 1, 2, and 3 (see Statistical analysis section) and sex (multivariable Cox analysis). Only variables with P<0.05 and the period are represented. (B) Study periods in the group of patients with depressed LVEF adjusted by all the management variables for which in this study and subgroup there were significant differences in prevalence between Periods 1, 2, and 3 plus age and sex (see Statistical analysis section) (multivariable Cox analysis). Only variables with P<0.05 and the period are represented. RR, relative risk.

 
Evolution of the clinical characteristics and survival of CHF patients with normal LVEF
LVEF was >50% in 442 of the 1110 patients for whom it was evaluated. Of these 442, 147 were admitted in Period 1, 109 in Period 2, and 186 in Period 3. As noted earlier, these figures correspond to an increase from 37 to 47% in the prevalence of normal LVEF among our patients.

The only major clinical criteria of CHF for which prevalence fell significantly in this group were jugular vein distension and cardiomegaly (Table 1), whereas the risk factors age, hypertension, and hyperlipidaemia all increased significantly (age by an average 3 years; hypertension from 54 to 69%; and hyperlipidaemia from 25 to 44%). There were significant increases in the prescription of beta-blockers, calcium channel blockers, and anticoagulants, but the increase in beta-blocker prescription was much less than that among patients with depressed systolic function, and there was no marked change in the prescription of ACE-Is or spironolactone. As among patients with LVEF <50%, however, prescription of digoxin fell steeply.

The risk of death within the follow-up period for patients with normal LVEF tended to rise during the study period (Figure 4, left-hand panel), but the rise was not statistically significant. The 1-year survival rates in Periods 1, 2, and 3 were 87.7, 85.6, and 81.0%, respectively. For these patients, the multivariable analyses identified age at admission (which increased during the study) and jugular vein distension (the prevalence of which fell) as increasing the risk of death independently of other clinical variables (Figure 6A) and similarly identified, among the diagnostic and therapeutic variables, prescription of ACE-Is or ARBs (neither of which changed in frequency during the study) as associated with improved survival, and prescription of digoxin (the use of which fell markedly) as associated with worse survival (Figure 6B). Clearly, for these patients, explication of the evolution of the survival data would require a more detailed analysis. However, as in the case of the patients with depressed LVEF, both the multivariable analyses confirmed that risk of death was not significantly influenced by the period in which admission had occurred except via the evolution of the variables identified as independent determinants in these analyses.



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Figure 6 (A) Study periods in the group of patients with normal LVEF adjusted by all the clinical variables for which in this study and subgroup there were significant differences in prevalence between periods 1, 2, and 3 (see Statistical analysis section) and sex (multivariable Cox analysis). Only variables with P<0.05 and period are represented. (B) Study periods in the group of patients with normal LVEF adjusted by all the management variables for which in this study and subgroup, there were significant differences in prevalence between periods 1, 2, and 3 (see Statistical analysis section) (multivariable Cox analysis) plus ACE-Is/ARB, age, and sex. Only variables with P<0.05 and the period are represented. RR, relative risk; JVD, jugular vein distension.

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Since 1991, the death rate among CHF patients admitted to our centre during the first year following hospitalization has fallen significantly by almost 8% among patients with LVEF <50%, but this decrease has not been accompanied by a parallel improvement in the prognosis of patients with LVEF ≥50%, whose chances of survival have in fact shown some signs of worsening. The improvement in the former group may be attributed to a reduction in clinical severity upon admission (i.e. to earlier diagnosis), but mostly to more generalized use of drugs that are now known to favour the survival of such patients; these factors seem to have prevailed against a simultaneous tendency towards a greater prevalence of risk factors, notably hyperlipidaemia. In the case of patients with normal LVEF, the prevalence of risk factors, including age, has increased more markedly; reductions in clinical severity have been less marked; and the increase in the intensity of medication has also been less pronounced, especially with regard to prescription of ACE-I and beta-blockers.

The proportion of CHF patients with normal LVEF is steadily increasing and is currently between 30 and 50%,18,19 depending on the type of sample studied. Although community studies have generally found normal LVEF to be associated with longer survival,2023 this has not been the case in most studies of hospitalized patients.24,25 In particular, the survival of the patients with normal LVEF included in the present study, when monitored over 12 years without regard to date of admission, does not differ significantly from that of the patients with depressed LVEF.26

Some recent papers have also reported a progressive decrease in the death rate among CHF patients,4,610 a development they attribute to earlier diagnosis and more widespread use of drugs now known to favour survival, ACE-Is, and beta-blockers in particular. With regard to the very-short-term death rate (12 weeks), as was observed in the European Heart Survey in Congestive Heart Failure, both ACE-Is and beta-blockers were associated with better survival among both patients with depressed LVEF and patients with normal LVEF;20 and increased prescription of ACE-Is and beta-blockers seems likely to have contributed to the improvement in 1-year mortality observed in this study among patients with depressed LVEF; but, as noted earlier, changes in drug prescription practice in our study (increased use of beta-blockers, calcium channel blockers, and anticoagulants) failed to bring about a significant improvement in the 1-year mortality of patients with normal LVEF.

Although adherence to clinical guidelines has been reported to reduce mortality and rehospitalization rates among CHF patients as a whole,27,28 clinical guidelines for the treatment of patients with normal LVEF are still to a large extent unsupported by statistical evidence, being based mainly on theoretical physiopathological reasoning.29,30 Recommended actions aim at the control of blood pressure and myocardial ischaemia, the prevention of tachycardia, the maintenance of sinus rhythm, and the regression of structural and functional cardiac alterations (hypertrophy, fibrosis, diastolic dysfunction). No clinical trials have provided reliable empirical evidence as to the most appropriate therapeutic strategy for these patients; for example, the results of CHARM-Preserved Trial found no significant difference between candesartan and placebo with regard to cardiovascular mortality and hospitalization for CHF.31 It is not even known for sure what the main causes of death among CHF patients with normal LVEF are (among patients with depressed LVEF, they are refractory CHF and sudden death): a recent study of the causes of clinical instability leading to hospitalization of these patients was only able to identify causes in half the cases considered, the main determinants identified being blood pressure surges (systolic blood pressure >200 mmHg), non-adherence to therapy, severe mitral or aortic valve regurgitation, acute coronary syndrome, kidney failure, and supraventricular arrhythmias (especially atrial fibrillation).32 This plurality of causes of hospitalization is presumably echoed by causes of death and suggests that in order to achieve a significant reduction in mortality among these patients, it will first be necessary to obtain much more precise information about their physiopathological condition and the influence of vascular and renal comorbidities associated with their CHF.

Study limitations
As the patients studied had all been hospitalized in the cardiology service of a university hospital, they may not be fully representative of the general CHF population. In particular, this may have been responsible for them being, on average, slightly younger than those involved in certain community studies or studies of patients hospitalized in other kinds of hospital or service and for a greater prevalence of men and of ischaemic heart disease and a smaller prevalence of comorbidity. It is possible that, for the same reason, therapeutic management may also have been somewhat better than in some other studies. In contrast, LVEF was not measured in all cases. However, it seems unlikely that any bias can have been introduced into the comparison of the two LVEF groups because the existence of LVEF measurements did not depend on factors differentiating these two groups, and the results of survival analysis for the whole group of 1281 patients for whom survival data were available did not differ significantly from the results of a parallel analysis including only the 962 for whom an LVEF measurement was also available.


    Conclusion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
In this study, we found that although the death rate among hospitalized CHF patients with depressed LVEF during the first year after discharge has tended to fall over the past 10 years (probably because of earlier diagnosis and more intense use of relevant drugs), in our centre, application of current clinical guidelines has led to no such decrease for patients with normal LVEF. This situation points to a need to reconsider the diagnostic and therapeutic strategy to be employed with this latter group of patients. It is to be hoped that clinical trials currently being carried out may provide some orientation in this respect.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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