Beta-blocker treatment of chronic systolic heart failure improves prognosis even in patients meeting one or more exclusion criteria of the MERIT-HF study

Andreas Jost1, Bernhard Rauch1,*, Matthias Hochadel1, Ralph Winkler1, Steffen Schneider1, Martina Jacobs1, Caroline Kilkowski1, Andreas Kilkowski1, Herbert Lorenz1, Kerstin Muth1, Christian Zugck2, Andrew Remppis2, Markus Haass3, Jochen Senges1 for the HELUMA study group

1Institut für Herzinfarktforschung, Herzzentrum Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen am Rhein, Germany
2Medizinische Klinik III, Universität Heidelberg, Heidelberg, Germany
3Abt. Kardiologie, Theresienkrankenhaus, Mannheim, Germany

Received 23 February 2005; revised 28 July 2005; accepted 4 August 2005; online publish-ahead-of-print 23 September 2005.

* Corresponding author. Tel: +49 621 5032850; fax: +49 621 5032899. E-mail address: rauchb{at}klilu.de


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Summary and conclusions
 References
 
Aims Improved prognosis of patients with chronic systolic heart failure by treatment with beta-blockers has been shown in several randomized controlled multicentre trials. However, in clinical practice only a part of heart failure patients meet the inclusion criteria of these trials. The present study evaluates whether reduction of mortality by beta-blockers also can be achieved in patients presenting one or more exclusion criteria of the MERIT-HF trial.

Methods and results From the Ludwigshafen Heart Failure Registry 675 patients with chronic systolic heart failure consecutively enrolled between January 1995 and June 2004 were divided in two groups either meeting the inclusion criteria of the MERIT-HF trial (‘trial patients’: n=278, 60% treated with beta-blockers) or not (‘non-trial patients’: n=397; 51% treated with beta-blockers). The distribution of the MERIT-HF exclusion criteria in the group of ‘non-trial patients’ was as follows: acute myocardial infarction 9.6%; systolic blood pressure <100 mmHg 7.5%; chronic obstructive lung disease 33.2%; other serious diseases potentially limiting prognosis 16.9%; acutely performed or planned ICD, bypass surgery, PCI, heart transplantation: 17.1, 15.9, 7.8, and 4.8%, respectively. Median follow-up was 31.3 months (upper/lower quartile 16.3/50.0 months). All-cause mortality was significantly reduced by beta-blocker treatment not only in ‘trial patients’ (adjusted hazard ratio 0.57, 95% CI 0.38–0.86) but also in ‘non-trial patients’ (adjusted hazard ratio 0.72, 95% CI 0.53–0.97).

Conclusion In clinical practice only the smaller part of the population to be treated for chronic systolic heart failure meets the inclusion criteria of the MERIT-HF study. However, beta-blocker treatment is associated with a significantly reduced long-term mortality even in patients meeting one or more exclusion criteria of the MERIT-HF study.

Key Words: Chronic systolic heart failure • Beta-blocker • Prognosis • MERIT-HF study • Registry


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Summary and conclusions
 References
 
Beta-blocker treatment of patients with chronic systolic heart failure is well established and strongly recommended in international guidelines for diagnosis and treatment of chronic heart failure.1,2 The basis of this recommendation are several randomized, placebo-controlled trials, which clearly have shown treatment with beta-blockers to significantly improve long-term survival of chronic heart failure patients.36

Evaluation of the clinical efficacy of any new pharmacological treatment requires almost experimental conditions within the clinical trials to reduce confounders that independently may interfere with clinical outcome. Therefore, study populations of clinical trials have to be characterized by well-defined inclusion and exclusion criteria. However, as shown recently, these experimental settings of placebo-controlled randomized trials do not necessarily reflect the conditions in clinical practice, in which the study group of patients may only represent a small part of the total population to be treated.7 In addition, outcome of controlled trials may be influenced by selection bias of participating patients, and close monitoring and higher levels of compliance of trial patients may independently be associated with an improved clinical course.8,9 Finally, restricting trial medication to patients meeting the specific inclusion criteria withholds potentially effective treatment from the large group of remaining patients. On the other hand, uncontrolled extension of trial medication to patients excluded from the trial also could be harmful.

On the basis of the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) and the Ludwigshafen Chronic Heart Failure Registry the present study therefore evaluates, (a) to what extent the population of the MERIT-HF trial reflects the patients‘characteristics of all-day care, (b) to what extent inclusion and exclusion criteria of the MERIT-HF study are considered in clinical practice, and (c) whether beta-blocker treatment not only is effective in patients who meet the inclusion criteria of the MERIT-HF study, but also in patients who have been excluded from this study.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Summary and conclusions
 References
 
Ludwigshafen chronic heart failure registry
The basis of the present study is the prospective Ludwigshafen Chronic Heart Failure Registry. This registry includes patients with chronic systolic heart failure, who initially were admitted to the Ludwigshafen Heart Center because of heart failure, and who gave their informed consent for participation in the registry. In the registry, pre-defined variables are collected from the patients and from the medical records. These variables include demographic data, patient's history, clinical presentation, medical therapy, electrocardiogram, holter monitoring, echocardiography, cardiopulmonary function tests, laboratory parameters, and coronary angiography. Follow-up information was obtained by a yearly telephone contact on the basis of a pre-defined questionnaire. If the patient could not be contacted, information was obtained by the general practitioner and in case of death by the local citizen registration authorities. Patient care during follow-up was primarily done by general practitioners and specialists of cardiology or internal medicine. Care by the Ludwigshafen Heart Center was restricted to patients hospitalized for worsening of heart failure, interventional therapy, or other reasons. Some patients with advanced heart failure, or patients with planned heart transplantation had additional care by the specialized heart failure advisory board organized by the Ludwigshafen Heart Center. No physician has been influenced in his treatment of chronic heart failure patients by the study committee.

Study population
Patients were enrolled between January 1995 and June 2004. The primary endpoint was defined as all-cause mortality. For persons who died, the follow-up time was defined as the time period between index admission (enrolment into the Ludwigshafen registry) and death. The follow-up time of surviving patients was calculated as the time period between admission and the last successful ascertainment of vital status. From the total population of the Ludwigshafen Chronic Heart Failure Registry the following patients were excluded from the present study:

  1. Patients already deceased during the initial hospital admission right after enrolment into the registry or without recorded follow-up.
  2. Patients with primary valvular or congenital heart disease as the leading cause of heart failure.
  3. Patients with any contraindications against beta-blocker treatment, and patients missing any of the inclusion criteria of the MERIT-HF study as listed below under ‘trial patients’.

According to these criteria a total of 675 patients could be included in the study, and this population was divided into the following two groups:

Trial patients
Study patients of the Ludwigshafen registry, whose basic characteristics were in accordance with the inclusion criteria of the original MERIT-HF study, and who did not meet any of the exclusion criteria of the original MERIT-HF study were defined as ‘trial patients’. In detail, these inclusion criteria were defined as follows (for comparison the original text of the MERIT-HF study is given in parenthesis, 3);

Non-trial patients
Patients of the Ludwigshafen registry fulfilling the inclusion criteria described above, but additionally presenting one or more of the original MERIT-HF exclusion criteria were defined as ‘non-trial patients’. In detail, the criteria for the population of ‘non-trial patients’ were defined as follows (for comparison the original text of the MERIT-HF study exclusion criteria is given in parenthesis, 3);

Patients treated with either diltiazem or verapamil also were excluded in the MERIT-HF study, but these drugs were generally not considered for treatment of heart failure patients within the Ludwigshafen Chronic Heart Failure Registry.

According to the previous definitions 278 patients (41%) of the study population fulfilled the inclusion criteria of the MERIT-HF study (‘trial patients’), whereas 397 (59%) patients fell into the group of ‘non-trial patients’. Table 2 shows the distribution of the above MERIT-HF exclusion criteria within the subgroup of ‘non-trial patients’ either receiving beta-blockers or not.


View this table:
[in this window]
[in a new window]
 
Table 2 Baseline characteristics of ‘non-trial patients’ within the Ludwigshafen Chronic Heart Failure Registry.
 
Statistical methods
Absolute numbers and percentages were computed to describe the study population. As in the original publication of the MERIT-HF study,3 the distribution of metrical variables is characterized by means and standard deviations. For descriptive purposes, groups were compared by Pearson {chi}2 test with respect to categorical variables, with respect to continuous variables by Wilcoxon rank-sum test, or by t-test, if only means and standard deviations were available. Crude survival functions for subgroups were estimated by Kaplan–Meier curves and compared by log-rank test. Their confidence intervals have been calculated using Greenwood's formula.

Taking into account the variability of the follow-up times the effect of beta-blocker treatment on all-cause mortality was evaluated by the Cox proportional-hazards model. As the central analysis of the present study adjusted hazard ratios were calculated together with their 95% confidence intervals separately within the subgroups of ‘trial patients’ and ‘non-trial patients’ in order to evaluate whether the results of the MERIT-HF study could be replicated in the group of ‘trial patients’ and extended to the group of ‘non-trial patients’.

The significance of the beta-blocker effect was tested by the Wald test, assuming a significance level of 0.05. The proportional hazard assumption for a factor was assessed graphically by judging the parallelity of log cumulative hazard curves in different strata defined by the factor levels. For multivariable models these curves were derived from Cox models stratified for the levels of the factor of interest with the remaining covariates included in the model.10

For adjustment, risk factors known for adverse outcome and potential confounders differently distributed between the beta-blocker and the non-beta-blocker groups were included. These were age, gender, NYHA class III/IV at discharge, ejection fraction ≤30%, ischaemic disease as primary cause of heart failure, diabetes, and statin treatment. In the group of ‘non-trial patients’ the following variables potentially affecting long-term prognosis were included in addition: concomitant disease limiting prognosis including chronic obstructive disease and interventional therapy during hospital stay or planned in future including coronary bypass grafting, coronary angioplasty, and ICD implantation.

All P-values are the result of two-tailed tests. The calculations were performed using the SAS statistical package, version 8.02 (SAS Institute, Cary, NC, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Summary and conclusions
 References
 
Study population
From the 675 patients of the Ludwigshafen Chronic Heart Failure Registry included in the study 370 patients (55%) received beta-blockers. Forty-one percent of the total population fulfilled the inclusion criteria of the original MERIT-HF study (‘trial patients’), whereas the majority of the study population (59%) had at least one of the exclusion criteria used in the MERIT-HF study (‘non-trial patients’). The distribution of the various beta-blockers for treatment of heart failure was as follows: metoprolol 77.0%, carvedilol 16.0%, bisoprolol 6.3%, others 0.7%. The registry data do not discriminate different formulations of metoprolol. However, metoprolol succinate is preferred in the vast majority of patients in the Ludwigshafen area.

In Table 1, the characteristics of the ‘trial patients’ of the Ludwigshafen Chronic Heart Failure Registry are compared with the characteristics of the patients included into the original MERIT-HF study.3 On an observational basis, the registry patients identified as ‘trial patients’ more often had non-ischaemic heart failure, history of hypertension, and more often were in NYHA class IV before enrolment into the registry (at hospital admission). In addition, when compared with the patients of the MERIT-HF study, ‘trial patients’ of the registry were more often treated with glycosides (ß-acetyldigoxin or digitoxin) and lipid lowering drugs (statins).


View this table:
[in this window]
[in a new window]
 
Table 1 Baseline characteristics of ‘trial patients’ within the Ludwigshafen Chronic Heart Failure Registry (left columns) and patients included into the original MERIT-HF study (right columns)
 
Table 1 also compares baseline characteristics of ‘trial patients’ either being treated with beta-blockers or not. ‘Trial patients’ on beta-blocker-therapy more often received lipid-lowering drugs (statins). All other baseline characteristics did not differ significantly between both groups.

The characteristics of ‘non-trial patients’ of the Ludwigshafen registry either receiving beta-blockers or not are outlined in Table 2. This table also includes the prevalence of MERIT-HF exclusion criteria in ‘non-trial patients’ (bold figures). Several parameters including MERIT-HF exclusion criteria were not equally distributed between the subgroups either being treated with beta-blockers or not.

Prognostic data
Three hundred and seven patients died during the follow-up period, 103 in the group of ‘trial patients’ and 204 in the group of ‘non-trial patients’. Median and interquartile range of the follow-up time was 39.4 (27.4–61.0) months for surviving patients, 19.5 (6.8–35.4) months for patients deceased, and 31.3 (16.3–50.0) months for the total group under investigation.

Figure 2 shows the Kaplan–Meier survival curves of ‘trial patients’ as compared to the group of ‘non-trial patients’. All-cause mortality after 3 years was significantly higher in the group of ‘non-trial patients’.



View larger version (12K):
[in this window]
[in a new window]
 
Figure 2 Kaplan–Meier survival curves comparing ‘trial patients’ (blue line) vs. ‘non-trial patients’ (red line) of the Ludwigshafen Chronic Heart Failure Registry.

 
Figure 3A and B show the effect of beta-blocker therapy in ‘trial patients’ and in ‘non-trial patients’. In both groups beta-blocker therapy was associated with significantly lower all-cause mortality during a follow-up of 3 years, but survival curves did not separate before 5–6 months after discharge (Figure 3A and B). Kaplan–Meier estimates of 1-, 2-, 3-year mortality of ‘trial patients’ and ‘non-trial patients’ either being treated with beta-blockers or not are given in Table 3. In Cox regression models stratification by gender was used in order to satisfy the proportional-hazards assumption. The adjusted hazard ratio for all-cause mortality was 0.57 (95% CI 0.38–0.86) for trial patients and 0.72 (95% CI 0.53–0.97) for ‘non-trial patients’.



View larger version (20K):
[in this window]
[in a new window]
 
Figure 3 (A) Kaplan–Meier survival curves comparing ‘trial patients’ of the Ludwigshafen Chronic Heart Failure Registry either being on chronic beta-blocker treatment (BB+, blue line) or not (BB–, red line). (B) Kaplan–Meier survival curves comparing ‘non-trial patients’ of the Ludwigshafen Chronic Heart Failure Registry either being on chronic beta-blocker treatment (BB+, blue line) or not (BB–, red line).

 

View this table:
[in this window]
[in a new window]
 
Table 3 Adjusted hazard ratios and Kaplan–Meier estimates of 1-, 2-, and 3-year all-cause mortality of the Ludwigshafen Chronic Heart Failure Registry
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Summary and conclusions
 References
 
In the present study the following major results were obtained:
  1. In clinical practice a large number of patients treated for chronic systolic heart failure do not meet the inclusion criteria of the MERIT-HF study (Figure 1).
  2. In the population of the Ludwigshafen registry, 40% of those patients fulfilling all inclusion criteria of the MERIT-HF study were not on beta-blocker treatment. Vice versa, in the group of ‘non-trial patients’ 51% were on beta-blocker treatment, despite every patient presented one or more exclusion criteria of the MERIT-HF trial (Figure 1).
  3. ‘Non-trial patients’ of the Ludwigshafen registry had a significantly higher long-term mortality than ‘trial patients’ (Figure 2), and this increased mortality could be observed in patients either being on beta-blocker treatment or not (Table 3). Moreover, mortality of ‘trial patients’ of the Ludwigshafen Registry was higher than mortality documented in the MERIT-HF study (Table 3).
  4. Not only in ‘trial patients’, but also in the group of ‘non-trial patients’ treatment with beta-blockers was independently associated with a significant reduction of all-cause mortality over a time period of approximately 3 years (Figure 3, Table 3).



View larger version (31K):
[in this window]
[in a new window]
 
Figure 1 Overview of the study population.

 
Translation of randomized controlled trials into clinical practice
Randomized controlled clinical trials are often based on almost ‘experimental’ conditions, in order to test efficacy of the treatment under investigation, and to exclude potential confounders. However, depending on the disease under investigation, a large part of patients seen in community-based practice may not meet the inclusion criteria of these trials. Consequently, the population of some randomized controlled trials may not be representative for the population of patients to be treated in clinical practice. In a recent study, only 18, 13, and 25% of older hospitalized heart failure patients met the inclusion criteria of the SOLVD, MERIT-HF, and RALES studies, respectively.7 In the present study, only 41% of the patients of interest could theoretically be included in the MERIT-HF study. Taking this into account, it is of interest to investigate whether the results of randomized controlled key trials can be extended to a larger group of patients more closely reflecting the population of interest under community-based conditions for the following reasons:
  1. According to the actual knowledge beta-blocker treatment is of fundamental importance in all patients with advanced chronic systolic heart failure, except that there are contraindications.
  2. As shown in the present study the extension of beta-blocker treatment beyond the inclusion criteria of the major clinical trials is already a clinical reality.
  3. On the other hand, in accordance with other surveys the present study also shows that many patients fulfilling the inclusion criteria of the large trials do not receive beta-blocker treatment, suggesting a considerable uncertainty in community-based medicine as to whether beta-blockers in chronic heart failure should be administered or not.11
  4. As long-term mortality of ‘non-trial patients’ was significantly higher than that of the group of ‘trial patients’ (Figure 2), it may be suggested that patients not being included in randomized trials often represent a high-risk population with a special need for optimal treatment.

The results of the present study strongly suggest that extension of beta-blocker treatment to a broader group of patients with chronic systolic heart failure, more closely representing the population of all-day care, is justified.

Long-term mortality: MERIT-HF study vs. Ludwigshafen registry
One-year mortality of ‘trial patients’ either being treated with beta-blockers or not, was higher when compared with the mortality of patients included in the MERIT-HF study (Table 3). This may be due to differences in the baseline characteristics (i.e. higher prevalence of registry patients presenting with NYHA class IV; a slightly lower mean ejection fraction of registry patients; Table 1), but a more close monitoring of patients included into the MERIT-HF trial also has to be taken into account. Improved outcome even in the placebo group of patients included in controlled trials is a well-known phenomenon,8,9 and especially in chronic heart failure patients close monitoring has been demonstrated to be effective in improving the clinical course.12

In the Ludwigshafen registry Kaplan–Meier survival curves of patients receiving beta-blockers or not exhibit a delayed separation in ‘trial patients’ and ‘non-trial patients’. In the MERIT-HF study, separation of survival curves was also delayed and did not occur before 3 months after randomization.3 Although this cannot conclusively be explained by the present data, the following factors may contribute to this observation: (a) medication of registry patients may not be as well controlled as in clinical trials, thereby potentially attenuating the beta-blocking effect, (b) slow up-titration or even failure of up-titration may also contribute to the observed late effect.

Methodological problems and study limitations
Choice of the reference trial
Although there are several major controlled trials that have positively tested treatment with either bisoprolol, carvedilol, and metoprolol in patients with chronic heart failure,35 the present evaluation has been restricted to the MERIT-HF study for the following reasons:

  1. Because of some variation of the inclusion and exclusion criteria in CIBIS-II, COPERNICUS, and MERIT-HF, inclusion of all three trials would have increased complexity of the present evaluation on the cost of transparency.
  2. Metoprolol was the beta-blocker mostly used for treating chronic heart failure patients in the present registry.
  3. With respect to survival of chronic heart failure patients the effect of bisoprolol, carvedilol, and metoprolol may be regarded to be similar, so that the MERIT-HF study may be taken as a representative for the other trials.

Still, it has to be taken in mind that effects and side effects of bisoprolol, carvedilol, and metoprolol may differ in their extent and in different subgroups of patients. A subgroup analysis considering the different types of beta-blockers used in this registry would not have been appropriate, as the subgroups are too small for adequate evaluation.

Study population
The group of ‘non-trial patients’ in the present study is not a heterogeneous group of all patients simply not fulfilling inclusion criteria of the MERIT-HF study. Apart from patients with contraindications for beta-blocker treatment, patients with primary valvular or congenital heart disease also have not been considered, as in these cases beta-blocker treatment has to be done on an individual basis depending on the nature of the disease. Furthermore, patients who already died during the initial hospitalization have been excluded, as the aim of the present study was to evaluate chronic beta-blocker treatment.

In accordance with the MERIT-HF trial the present study also excludes patients of low risk (NYHA class I, ejection fraction >40%), patients not under treatment with ACE-inhibitors and diuretics, and patients <40 and >80 years of age. These additional exclusion criteria were chosen for the following reasons:

  1. In a low risk population the effect on survival of beta-blocker treatment in addition to ACE-inhibitors can be expected to be small, requiring a larger number of patients to be evaluated.
  2. Patients not under treatment with ACE-inhibitors and diuretics were excluded from the study, as beta-blocker treatment in heart failure patients until now has been tested on top of ACE-inhibitors and diuretics.35
  3. Heart failure patients aged between 40 and 80 represent the vast majority of chronic heart failure patients in the Ludwigshafen registry.

Beta-blocker treatment of patients in the Ludwigshafen registry
The present study does not discriminate individual reasons for treating heart failure patients with beta-blockers or not, as this was not the primary aim of the study. Furthermore, the study neither reflects the severity of concomitant disease, nor the individual side effects influencing treatment with beta-blockers. Therefore, in the present study treatment of patients with beta-blockers has to be regarded as a result of multiple factors influencing the decision of the treating physician. These factors include knowledge, clinical experience, specialization, and the whole variety of serious and non-serious side effects being experienced by the patient. Apart from these considerations, it is of interest that almost one-quarter of ‘non-trial patients’ receiving beta-blocker treatment had chronic obstructive lung disease as defined by the Global Initiative for Chronic Obstructive Lung Disease,13 suggesting a beneficial effect of beta-blockers even in these patients. On the basis of a careful pulmonary diagnostic evaluation and control, beta-blocker treatment of patients with chronic systolic heart failure may therefore be extended to patients with chronic obstructive lung disease.


    Summary and conclusions
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Summary and conclusions
 References
 
Improvement of prognosis of patients with chronic heart failure by beta-blocker treatment has been shown by several randomized controlled multicentre trials. However, in clinical practice only the smaller part of chronic heart failure patients meets the inclusion criteria of these trials. The presented data demonstrate that chronic beta-blocker treatment is effective in reducing long-term mortality even in patients presenting with one or more exclusion criteria of one representative of these trials, the MERIT-HF study. Under controlled conditions chronic application of beta-blockers in a broader population of chronic systolic heart failure patients therefore appears to be justified. This may even include patients with correctly diagnosed chronic obstructive lung disease.

Conflict of interest: none declared.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Summary and conclusions
 References
 

  1. Remme WJ and Swedberg K (Co-chairmen), Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527–1560.[Free Full Text]
  2. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee to revise the 1995 guidelines for the evaluation and management of heart failure). Circulation 2001;104:2996–3007.[Free Full Text]
  3. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–2007.[CrossRef][ISI][Medline]
  4. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. Lancet 1999;353:9–13.[CrossRef][ISI][Medline]
  5. Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL, for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1659–1665.[Abstract/Free Full Text]
  6. The Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659–1667.[Abstract/Free Full Text]
  7. Masoudi FA, Havranek EP, Wolfe P, Gross CP, Rathore SS, Steiner JF, Ordin DL, Krumholz HM. Most hospitalized older persons do not meet the enrolment criteria for clinical trials in heart failure. Am Heart J 2003;146:250–257.[CrossRef][ISI][Medline]
  8. Van Bergen PF, Jonker JJ, Molhoek GP, van der Burgh PH, van Domburg RT, Deckers JW, Hofman A. Characteristics and prognosis of non-participants of a multi-centre trial of long-term anticoagulant treatment after myocardial infarction. Int J Cardiol 1995;49:135–141.[CrossRef][ISI][Medline]
  9. Albert SM, Sano M, Marder K, Jacobs DM, Brandt J, Albert M, Stern Y. Participation in clinical trials and long-term outcomes in Alzheimer‘s disease. Neurology 1997;49:38–43.[Abstract]
  10. Andersen PK. Testing goodness of fit of Cox's regression and life model. Biometrics 1982;38:67–77.[ISI]
  11. Cleland JG, Cohen-Solal A, Cosin Aguilar J, Dietz R, Eastaugh J, Follath F, Freemantle N, Gavazzi A, van Gilst WH, Hobbs FDR, Korewicki J, Madeira HC, Preda I, Swedberg K, Widimsky J, for the IMPROVEMENT of Heart Failure Programme Committees and Investi Cleland JGF. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey. Lancet 2002;360:1631–1639.[CrossRef][ISI][Medline]
  12. J. Gonseth J, Guallar-Castillon P, Banegas JR. The effectiveness of disease management programmes in reducing hospital re-admission in older patients with heart failure: a systematic review and meta-analysis of published reports. Eur Heart J 2004;25:1570–1595.[Abstract/Free Full Text]
  13. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2005; http://www.goldcopd.com




This Article
Abstract
Full Text (PDF)
All Versions of this Article:
26/24/2689    most recent
ehi473v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Request Permissions
Google Scholar
Articles by Jost, A.
PubMed
PubMed Citation
Articles by Jost, A.