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European Heart Journal Advance Access published online on November 8, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn498
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Effects of annual influenza vaccination on winter mortality in elderly people with chronic heart disease

Cinta de Diego1,*, Angel Vila-Córcoles1, Olga Ochoa1, Teresa Rodriguez-Blanco2, Elisabeth Salsench1, Imma Hospital1, Ferran Bejarano1, M. del Puy Muniain1, Mercé Fortin1, Montserrat Canals1 and EPIVAC Study Group1

1 Primary Care Service of Tarragona-Valls, Institut Català de la Salut, Prat de la Riba 39, Tarragona 43001, Catalonia, Spain
2 Department of Statistic and Epidemiology of IDIAP Jordi Gol i Gurina, Barcelona, Spain

Received 4 December 2007; revised 13 October 2008; accepted 16 October 2008.

* Corresponding author. Tel: +34 977240666, Fax: +34 977226411, Email: cintaddc{at}tinet.org


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 Appendix: Author contributions
 Acknowledgements
 References
 
Aims: Although there is general agreement for the recommendation of the influenza vaccine to elderly and high-risk adults, the magnitude of clinical effectiveness and benefit from the annual vaccination is controversial. In this study, we have assessed the effects of annual influenza vaccination on winter mortality in older adults with chronic heart disease.

Methods and results: Cohort study that included 1340 Spanish community-dwelling individuals 65 years or older who had chronic heart disease (congestive heart failure or coronary artery disease) followed from January 2002 to April 2005. Annual influenza vaccine status was a time-varying condition and primary outcome was all-cause death during the study period. Multivariable Cox proportional-hazard models adjusted by age, sex, and comorbidity were used to evaluate vaccine effectiveness. Influenza vaccination was associated with a significant reduction of 37% in the adjusted risk of winter mortality during the overall period 2002–2005. The attributable mortality risk reduction in vaccinated people was 8.2 deaths per 1000 person-winters. We estimated that one death was prevented for every 122 annual vaccinations (ranging between 49 in Winter 2005 and 455 in Winter 2003).

Conclusion: Our results suggest a benefit from the influenza vaccination and support an annual vaccination strategy for elderly people with cardiac diseases.

Key Words: Influenza vaccine • Effectiveness • Elderly • Heart disease • Mortality


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 Appendix: Author contributions
 Acknowledgements
 References
 
Influenza viruses are a major determinant of morbidity and mortality mainly caused by respiratory disease. The incidence of flu is higher in children and younger adults than in older individuals, but influenza-associated morbidity and mortality increase with age, especially for individuals with underlying medical conditions such as chronic heart diseases.1–3

During influenza epidemics, it has been reported that this viral infection was associated with increased death rates from cardiovascular diseases and a rise in autopsy-confirmed coronary deaths.4 Clinical and experimental data suggest that autoimmune mechanisms are responsible for accelerated coronary atherosclerosis in influenza infection. Both cellular and humoral autoimmune modes could participate in the onset or progression of atherosclerotic lesions due to influenza infection.5,6

To date, although some studies have reported that influenza infection causes excess specific cardiac mortality,4,7 the effect of the influenza vaccination in preventing mortality among patients with chronic heart diseases is not well known. This is because few studies have specifically focused on these patients8–10 and their conclusions were not always in favour of vaccination.10

On the other hand, although the effectiveness of the influenza vaccination in preventing mortality has been extensively studied among hospitalized or institutionalized patients during severe influenza seasons, few large studies have systematically evaluated the clinical benefit of vaccination in community-dwelling individuals over the medium or long term,11–15 and little is known about the effectiveness of the annual vaccination programmes in high-risk elderly people living in the community.

To assess influenza vaccine effectiveness in preventing mortality, we conducted a cohort study of 11 240 Spanish community-dwelling elderly individuals followed between 2002 and 2005. The analysis on vaccine effectiveness covering the general elderly and chronic obstructive pulmonary disease patients has been published.15,16 In the present study, we assessed the relationship between the annual influenza vaccine status and all-cause winter mortality among a group of 1340 individuals with chronic heart disease.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 Appendix: Author contributions
 Acknowledgements
 References
 
Design, setting, and study population
We conducted a cohort study that included all community-dwelling individuals 65 years or older assigned to eight Primary Health Care Centres (PHCCs) in the region of Tarragona (Catalonia, Spain) who had a diagnosis of chronic heart disease (including heart failure or coronary artery disease) registered in their clinical record at the start of the study.

When the study started, the Health District of Tarragona had 12 PHCCs with an overall assigned population of 134 232 all-age inhabitants. The selection of the eight participating PHCCs was not randomized and they were chosen taking into account the existence of electronic clinical registries working since 1998 or before. The other four PHCCs in the Health District were not included because they had only computerized the clinical records more recently.

The 1340 cohort members were followed from the beginning of the study (1 January 2002) until enrolment from the PHCC ceased, the occurrence of death, or until the end of the study (30 April 2005). The study was approved by the Ethical Committee of the Catalonian Health Institute and conducted in accordance with the general principles for observational studies.

Sources of data
All participating PHCCs have an institutional computerized clinical record system which contains registries of immunizations, laboratory tests, medication prescription, diagnoses associated with outpatient visits, and chronic diseases coded according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9). The electronic records of each cohort member were used to identify whether the individual had received or not the influenza vaccine in each influenza vaccination campaign, and it was also used to identify the presence of chronic heart disease (heart failure: ICD-9 codes 428, 428.0 and 428.1; coronary artery disease: ICD-9 codes 410–414), co-morbidities, and other medical conditions.

Outcome measure and definitions
The influenza period was defined as the period during which influenza-like illnesses were frequently reported in the study area, from 1 January to 30 April for each year of the study.15

Primary outcome was all-cause death. Deaths were initially identified in the Institutional Demographic Database (which is updated monthly with administrative data about deaths, patients who have moved or new patients assigned to a PHCC). Afterwards, a review of the reference Civil Registry Offices of the eight PHCCs was used to identify those deaths that had occurred in cohort patients who had not been registered in the Institutional Database. This review was also used to validate the exact date of death in all cases. Finally, deaths were classified as occurring within the influenza period (January–April) or within a reference control summer period (June–September).

Exposure to influenza vaccination
For each year, information on the influenza vaccination status of the subjects was determined by a review of the PHCCs’ clinical records, which contain specially designated fields for annual influenza vaccinations. We assumed that information in clinical records was complete, so a subject was considered as non-vaccinated when data on vaccination was missing or vaccination was not recorded (in other words, a patient was considered as non-vaccinated when the specific field for annual vaccination was empty).

Influenza vaccine status was considered as a dichotomous (vaccinated or non-vaccinated) time-varying condition throughout the study period (i.e. in the analysis covering the overall study period, the same person could be considered non-vaccinated in 2002, vaccinated in 2003, and non-vaccinated in 2004 according to the reception or not of the influenza vaccine in the prior autumn).

Covariates
Covariates included dichotomous variables for sex, chronic lung disease (including asthma, emphysema, or chronic bronchitis), diabetes mellitus, hypertension, obesity, current smoking, and immunocompromised status. Age and the number of outpatient visits in the previous 2 years were considered as continuous covariates. Immunocompromise was a composite variable defined by the presence of any one of the following: cancer (solid organ or haematological neoplasia), chronic severe nephropathy (nephrotic syndrome, renal failure, dialysis, or transplantation), chronic severe liver disease (cirrhosis), anatomical or functional asplenia, AIDS, and long-term corticosteroid therapy (20 mg/day of prednisone) or another immunosuppressive medication. The presence of co-morbid conditions was determined by a review of the diagnosis codes in the electronic clinical record of each cohort member.

Statistical analysis
Incidence rates (IR) of death were calculated as person-years and person-weeks. For the numerator we used number of deaths. The denominator was the total number of person-years/person-weeks of observation for each study period considered. So, for each individual we determine the amount of observation time contributed to that period and to add up those contributions for all cohort members. Attributable risk (AR) was the difference between IR among vaccinated and non-vaccinated subjects (AR=IR exposed – IR non-exposed). Numbers needed to be vaccinated (NNV) to save one death were estimated for influenza periods (January–April = 17.1 weeks) and were calculated as the inverse of the AR (NNV=1/AR).16

The differences between groups were evaluated by means of the {chi}2 test for categorical variables and Student’s t-test for continuous variables.

Multivariate Cox proportional-hazards models were used to evaluate the association between receiving influenza vaccine and the time to death during the study period. We performed stratified analysis by influenza period (defined from January to April) and a reference non-influenza period (from June to September) of the overall study period and four supplementary analyses of the influenza season of each year. Influenza vaccine status was a time-varying covariate in the stratified analysis by influenza period and a dichotomous fixed condition (vaccinated/non-vaccinated in the previous autumn) in the analysis of each year.

The variables that have been considered in all the initial models are: age, sex, number of outpatient visits in the previous 2 years, chronic lung disease, diabetes, hypertension, obesity, smoking, and immunocompetence. The method to select a subset of covariates to include in the final proportional-hazards regression model is the purposeful selection.17 Age and sex have been judged epidemiologically relevant variables, being included in all the final models. The authors checked for confounders (change-in-estimate ≥ 20%), interactions, and multicolinearity among the independent variables. In addition, all the models have been compared by the partial likelihood ratio test and the Akaike’s information criterion (AIC). The proportional-hazard assumptions were assessed, adding the covariate by time interactions to the model and plotting the scaled and smoothed Schöenfeld residuals obtained from the main effects model. All results were expressed with 95% confidence intervals (CIs). Statistical significance was set at P < 0.05 (two-tailed). The analyses were performed using Stata/SE version 9.1 (Stata Corp.).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 Appendix: Author contributions
 Acknowledgements
 References
 
During the total study period, the 1340 cohort members were observed for an amount of 4027 person-years (209 968 person-weeks). The mean age when the study started was 76.2 years (SD: 7.1) and 47.4% were men. At baseline, 1068 (82.3%) of patients had some other form of co-morbidity, mostly hypertension (64.5%), diabetes mellitus (32.3%), or chronic lung disease (19.3%). Table 1 shows the characteristics of the Study Population when the study started (1 January 2002) according to the reception or non-reception of the influenza vaccine in the Autumn 2001. As it can be seen in Table 1, at the beginning of the study, vaccinated subjects were slightly older than non-vaccinated subjects (mean age: 76.7 vs. 75.5; P = 0.004), and they had more frequency of attendance and co-morbidity than non-vaccinated subjects.


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  		Table 1 Characteristics of the study population according to their influenza vaccine status at starting of the study (1 January 2002)

 
Of the 1340 cohort members, 277 (20.7%) died during the total 40 months follow-up, and 16 (1.2%) moved during the study period. Figure 1 shows the survival of cohort members throughout the 40 months study period.


Figure 1
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  		Figure 1 A survival flow chart of cohort members during the 40 month study period.

 
If we consider those cohort members who remained in the closed cohort at the beginning of each year (excluding patients who died or moved during the prior year), the annual vaccination coverage reached 64.2% in the winter 2002, 69.3% in 2003, 73.5% in 2004, and 72.3% in 2005. In total 83 196 person-weeks were observed within the overall January–April periods 2002–2005, of which 57 980 person-weeks (69.7%) were vaccinated and 25 216 person-weeks were non-vaccinated against influenza in the respective previous autumn.

The mean incidence rate of all-cause death throughout the total 40 months study period was 68.8 deaths per 1000 person-years (132 per 100 000 person-weeks). Mortality varied significantly throughout the months of the year. We observed 134 deaths within the influenza periods of January–April and 75 deaths during the reference summer periods (June–September).

Among the total 134 deaths occurring within January–April, cause-specific death was registered in the primary care clinical record in only 82 cases (61.2%). Among these 82 patients, the specific cause of death was a cardiovascular disorder in 28 cases (34.1%), a cancer in 24 cases (29.3%), a respiratory cause in seven cases (8.5%), an infectious cause in six cases (7.3%), and other causes in 17 cases (20.7%).

Considering the overall influenza periods 2002–2005, 85 deaths were observed among persons who had received the influenza vaccine in the prior autumn and 49 deaths among persons who had not received the vaccine in the previous autumn. This meant an all-cause mortality rate (per 100 000 person-weeks) of 146.6 (95% CI: 117–181) in vaccinated subjects and 194.3 (95% CI: 144–257) in non-vaccinated subjects. Table 2 shows the absolute number of deaths, mortality rates, and different results of the influenza vaccine’s effectiveness in reducing mortality risk within the influenza periods (January–April) and within the reference non-influenza periods (June–September).


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  		Table 2 Incidence and risk of all-cause mortality among elderly people with chronic cardiopathy within the influenza epidemic period and reference summer period, according to the reception of the influenza vaccine in the prior autumna

 
Unadjusted analysis showed that influenza vaccination was associated with a marginally significant decreasing rate of mortality within the overall influenza periods [hazard ratio (HR): 0.75; 95% CI: 0.52–1.06; P = 0.101], whereas it was not significant during the June–September control period (HR: 1.15; 95% CI: 0.68–1.90; P = 0.630).

Considering the sum of influenza periods 2002–2005, attributable risk among non-vaccinated subjects was 47.7 deaths per 100 000 person-weeks, so the number needed to vaccinate to save one death during one influenza period was 122 annual vaccinations (95% CI: 53 to infinite).

Multivariable analyses showed that annual vaccination was associated with a statistically significant reduction in the risk of all-cause mortality of 37% throughout the overall influenza periods 2002–2005 (adjusted HR: 0.63; 95% CI: 0.44–0.91; P = 0.013), whereas it was not significant during the reference summer period (adjusted HR: 0.94; 95% CI: 0.56–1.58; P = 0.814).

When we consider vaccine impact on winter mortality in each of the four analysed influenza seasons, the unadjusted protective effect of vaccination ranged from –8 to 40% (Table 3). Although the upper limit of the confidence interval did not reach statistical significance, we estimated that the numbers needed of annual vaccinations to save one death within each influenza period were 99 in the 2001–2002 influenza season, 455 in the 2002–2003 influenza season, 162 in the 2003–2004 influenza season, and 49 in the 2004–2005 influenza season.


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  		Table 3 Incidence and risk of all-cause mortality among the study population during influenza periods 2002–2005 according to Influenza Vaccine Statusa

 
Multivariable analysis showed that the adjusted effectiveness of vaccination against winter mortality varied between 20% in the 2002–2003 influenza season (adjusted HR: 0.80; 95% CI: 0.36–1.76; P = 0.572) to 54% in the 2001–2002 influenza season (adjusted HR: 0.46; 95% CI: 0.21–1.03; P = 0.059) (Table 3).

In supplementary analyses by sex, table not shown, vaccine effectiveness did not reach statistical significance in men. Vaccination effectiveness within the overall influenza period 2002–2005 was found in women (HR: 0.49; 95% CI: 0.30–0.78; P = 0.003). In stratified analyses by year, no statistically significant effect was observed in men, whereas a marginally significant effect was found in women in Winter 2002 (HR: 0.32; 95% CI: 0.10–1.04; P = 0.059) and 2005 (HR: 0.49; 95% CI: 0.23–1.02; P = 0.058).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 Appendix: Author contributions
 Acknowledgements
 References
 
Nowadays, there is a general agreement for the recommendation of the influenza vaccine to elderly and high-risk adults.2,3 However, the magnitude of clinical effectiveness and benefit from the annual vaccination campaigns is controversial.14,18

In this study, we have assessed the effects of the annual influenza vaccination on winter mortality in older adults with chronic heart disease (basically congestive heart failure and/or coronary artery disease). Although it was not randomized, the relatively large size of the study population together with the adjustment for important covariates in the multivariable analysis, provides an adequate basis for assessing the effects of the influenza vaccine status on winter mortality throughout a time-period with different severity of influenza seasons.

In the present study, annual influenza vaccine coverages varied from 64 to 74%, which is consistent with data reported for elderly people with chronic heart diseases in Spain and other developed countries, which have reported that approximately 30% of these subjects are not annually immunized against influenza.2,19,20

In this study, the influenza vaccination was associated with a nearly significant reduction of 25% in the unadjusted rate of all-cause winter mortality in vaccinated subjects, whereas the multivariable analysis showed a significant effectiveness of 37% (9–56%) in decreasing the risk of winter mortality throughout the overall study period among those patients who had received influenza vaccine in the prior autumn. Our result fits with those recently reported by Voordouw et al.13 in a retrospective cohort study focussed on people over 65 in the Netherlands, who found that the annual influenza vaccination was associated with an all-cause mortality risk reduction of approximately 24% during the overall study period and 28% during the epidemic periods.

Although a benefit of the influenza vaccination to prevent hospitalization and death has been largely reported, the effectiveness of the vaccine is not well understood for major cause-specific mortality, except pneumonia. Recently, Wang et al.7 have analysed 10 months mortality data of 102 692 individuals aged 65 years or older in Southern Taiwan, reporting that the influenza vaccination was significantly associated with a 44% lower risk of all-cause mortality and they have also reported a significant 22% reduction in the risk of death from heart diseases among vaccinated subjects.

In our study, cause specific mortality was not available in 39% of cohort members who died during the study period and furthermore, in some patients the cause of death was not specific enough to classify as influenza-related mortality or not. Thus, we have chosen all cause mortality as the main outcome measure, taking into consideration a possible misclassification bias and a lack of statistical power from an analysis of specific mortality. Given the difficulty for laboratory confirmed diagnosis of influenza infections, all-cause death has been considered an acceptable outcome to evaluate influenza vaccine effectiveness in many observational studies and meta-analyses.21,22 In favour of choosing all-cause mortality as the outcome to assess the effect of influenza vaccination on mortality is the difficulty to classify a death as influenza-related mortality and, consequently, the possibility of misclassification bias when cause-specific mortality is considered. In general, when the event of interest is death, all-cause mortality is considered a more robust event than cause specific mortality. Nevertheless, we emphasize that, given that specific mortality was not evaluated, a residual confounding in the estimates of vaccine effectiveness cannot be completely excluded.

The effectiveness of the influenza vaccine to decrease all-cause mortality is controversial, and nowadays there is disagreement about the magnitude of the protective effects from the vaccination. In a classical meta-analysis, Gross et al.21 estimated that influenza vaccine effectiveness against all-cause mortality varied from 27 to 30% in case–control studies to 56–76% in cohort studies. In a meta-analysis focused on elderly people living in the community, Vu et al.22 estimated vaccine effectiveness against all-cause mortality as 45–56%. Simonsen et al.18 have analysed influenza vaccine coverages and the estimates of influenza-related mortality and all-cause deaths for 33 influenza seasons from 1968 to 2001 in the USA elderly population. They reported that there was no correlation between increasing vaccination coverage after 1980 with declining mortality rates in any age group and concluded that many studies substantially overestimated the benefits of vaccination.18

In the present study, the difference between all-cause mortality in non-vaccinated and vaccinated subjects (attributable risk) was 47.7 deaths per 100 000 person-weeks during the overall January–April period, and we estimated that in the total population one winter death was prevented for every 122 annual influenza vaccinations, although this estimation does not exclude the possibility of a greater number since the value of the upper limits in the confidence interval reached infinite.

Important aspects that determine vaccine effectiveness are the intensity of viruses circulating during the study periods and the similarity between vaccine strains and circulating strains.23 During our study period (2002–2005), influenza activity in northern hemisphere countries was mild-to-moderate in most countries, and was associated with a mixed circulation of Virus A and Virus B. In this period, vaccine strains and the predominant circulating strain (mainly A[H3N2]) generally were well matched.24–27 In the study area, during the study period, the mean incidence rates of influenza-like illness reported between January and April among the overall population in the eight participating PHCCs were 63.4 cases per 100 000 person-weeks in 2002, 14.0 in 2003, 13.6 in 2004, and 84.3 in 2005.15 Our findings are epidemiologically plausible considering that, as it can be expected, in the present study the greatest level of vaccine effectiveness was observed in the winters with the highest influenza epidemic activity (2002 and 2005) where unadjusted vaccine effectiveness was 40 and 38% (with NNVs ranging from 49 to 99), whereas the lowest vaccine effectiveness occurred in those winters with lower epidemic activity (2003 and 2004) where unadjusted vaccine effectiveness reached only –8 and 22% (with NNVs ranging between 162 and 455).

Our study has several strengths. Vaccination was evaluated by survival analysis methods to estimate vaccine effectiveness adjusted for age and co-morbidity. The study was population-based and study population was large enough to evaluate the relationship between annual influenza vaccine status and winter mortality throughout the overall study period. On the other hand, the sample size was small in assessing vaccine effectiveness separately for each influenza season. The study also has some intrinsic limitations and to interpret our findings, some characteristics of the study need to be addressed. In this study, influenza vaccination was considered as a simple dichotomous variable (‘vaccinated’ or ‘non-vaccinated’) in each year, but other categories of influenza vaccine status (such as ‘first vaccination’, ‘revaccination’, ‘vaccination interruption’, or ‘vaccination restart’) which can influence vaccine effects were not evaluated.13

The main limitation of observational designs is a possible selection bias. In our study, vaccinated subjects were older and had more co-morbidity than non-vaccinated subjects (Table 1). Moreover those patients who had a higher number of underlying conditions had more visits than those patients who did have not, and this meant a higher probability of vaccination. However, in Spain all individuals are assigned to a PHCC and a free influenza vaccine is offered each autumn for all individuals over 65 years. We account for differences between vaccinated and non-vaccinated subjects in the analysis, by adjusting for these variables in the multivariable Cox proportional hazard model. However, as with all observational studies, the possible influence of residual confounding due to unknown confounding factors on the estimates of vaccine effectiveness cannot be completely excluded (Szklo M., Nieto J., 2000). Information bias may have occurred if some co-morbidity or vaccination was not recorded, but such misclassification would likely be random because vaccination and covariates were recorded before occurrence of death.

The efficacy of influenza vaccination and the estimated impact of annual influenza epidemics on morbid-mortality have been the basis for implementing influenza vaccination programmes for elderly and high-risk individuals.2,3,21,22 However, the effectiveness of vaccination has been reported to decrease in older age-groups and high-risk persons, and the magnitude of clinical effectiveness of annual vaccination campaigns is unclear. Nowadays, in this field, the gold standard of a large randomized controlled trial would be unethical and non-experimental studies evaluating influenza vaccination effectiveness must be applied.23,28 Our results show that the reception of the annual conventional inactivated influenza vaccine was associated with a significant low risk of all-cause winter mortality among community-dwelling elderly patients with chronic heart disease followed throughout a consecutive 4 year series that included four influenza seasons.

Our data confirms the benefit of the influenza vaccination, even considering mild-or-moderate severity of influenza seasons, and it supports an annual vaccination strategy for these patients. It must not be forgotten that approximately one-third of elderly patients with chronic heart diseases remain annually non-vaccinated, and the increase in vaccination uptakes should be a major goal in the care of these patients.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
Appendix: Author contributions
 Acknowledgements
 References
 
This study was supported by Grants from the Health Research Fund (FIS) of the Spanish Ministry of Health and Consumer Affairs (Madrid, FIS PI-021117) and the Jordi Gol Foundation, Barcelona.


   Appendix: Author contributions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Appendix: Author contributions
Acknowledgements
 References
 
C.D., A.V.-C., O.O., E.S., I.H., and F.B. designed the study, assessed outcomes, and wrote and edited the paper. A.V.-C. co-ordinated the study; C.D., O.O., M.M., M.F., and M.C. obtained the data; T.R.-B. did statistical analysis.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Appendix: Author contributions
 Acknowledgements
References
 
The authors thank V. Arija for her help in the statistical analysis. The authors also thank Joan Fort and Timothy Bowring for their help in the production of this paper. The authors would like to thank all the family physicians and nurses of the Primary Care Centres in Tarragona-Valls who collaborated in this study.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Appendix: Author contributions
 Acknowledgements
 References
 

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FLU SHOT OR NOT IN CHRONIC HEART FAILURE
Mitja Lainscak, et al.
European Heart Journal, 14 Oct 2009 [Full text]
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