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European Journal of Heart Failure 2004 6(4):453-461; doi:10.1016/j.ejheart.2004.02.003
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© 2004 European Society of Cardiology

Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC){star}

A. Bergströma, B. Anderssonb, M. Ednerc, E. Nylandera, H. Perssonc and U. Dahlströma,*

a Department of Cardiology and Physiology, University Hospital Linköping SE-58185 Linköping, Sweden
b Department of Cardiology, Sahlgrenska University Hospital Göteborg, Sweden
c Section of Cardiology, Division of Internal Medicine, Karolinska Institutet, Danderyd Hospital Stockholm, Sweden

* Corresponding author. Tel.: +46-13-22-20-00. E-mail address: ulf.dahlstrom{at}lio.se


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 References
 
Aim: The purpose of this study was to investigate the effects of carvedilol on diastolic function (DF) in heart failure patients with preserved left ventricular (LV) systolic function and abnormal DF.

Patients and Methods: We randomised 113 patients with diastolic heart failure (DHF) (symptomatic, with normal systolic LV function and abnormal DF) into a double blind multi-centre study. The patients received either carvedilol or matching placebo in addition to conventional treatment. After uptitration, treatment was continued for 6 months. Two-dimensional and Doppler echocardiography were used for quantification of LV function at baseline and at follow-up. Four different DF variables were evaluated by Doppler echocardiography: mitral flow E:A ratio, deceleration time (DT), isovolumic relaxation time (IVRT) and the ratio of systolic/diastolic pulmonary venous flow velocity (pv-S/D). Primary endpoint was change in the integrated quantitative assessment of all four variables during the study.

Results: Ninety-seven patients completed the study. A mitral flow pattern reflecting a relaxation abnormality was recorded in 95 patients. There was no effect on the primary endpoint, although a trend towards a better effect in carvedilol treated patients was noticed in patients with heart rates above 71 beats per minute. At the end of the study, there was a statistically significant improvement in E:A ratio in patients treated with carvedilol (0.72 to 0.83) vs. placebo (0.71 to 0.76), P<0.05.

Conclusions: Treatment with carvedilol resulted in a significant improvement in E:A ratio in patients with heart failure due to a LV relaxation abnormality. E:A ratio was found to be the most useful variable to identify diastolic dysfunction in this patient population. This effect was observed particularly in patients with higher heart rates at baseline.

Key Words: Diastolic heart failure • Carvedilol • Placebo-controlled • Non-invasive • E:A ratio

Received June 27, 2003; Revised December 22, 2003; Accepted February 5, 2004


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 References
 
Traditionally heart failure (HF) has been attributed to a decreased systolic left ventricular (LV) function, usually accompanied by an increase in left ventricular filling pressure and/or volume [1]. However, over the past 10 years it has become clear, that in 20–30% of patients, systolic function is normal and diastolic LV dysfunction might have led to the clinical manifestation of HF [2–4]. There is no doubt today that diastolic heart failure (DHF) is a pathophysiological clinical condition, distinct from or concomitant with systolic HF [5,6]. Diastolic dysfunction can be suspected in patients with signs and symptoms of HF and a normal or mildly reduced systolic LV ejection fraction (EF) >40% and normal LV end-diastolic volumes [6].

LV diastolic dysfunction may arise as a consequence of various underlying conditions that result in a modification of the physical properties of the myocardium. These conditions include hypertension, diabetes and chronic ischemic heart disease, in summary conditions which cause a structural impairment of the heart [7,8]. Usually LV diastolic dysfunction shortly precedes systolic dysfunction, but can also be present for a longer period of time (years). Impairment of diastolic function (DF) appears to be age-related [9,10] and data suggest that while ≤10% of patients with HF below the age of 50 years have diastolic dysfunction, this rises to 70% in patients aged over 80 years [11,12].

LVEF is most commonly used as a global variable to assess systolic function. However, there is no generally accepted single variable for indicating diastolic dysfunction [13] as measurements can be complicated by progression of the disease, ageing [14,15] and heart rate [16,17]. Different, and sometimes opposite, deviations from normal diastolic variables will be seen depending on whether the abnormality affects relaxation in initial diastole, or is mainly affecting LV compliance, apparent at end-diastole. For example, patients with abnormal LV relaxation may develop an elevation in left atrial pressure as the disease progresses, which tends to normalise some of the Doppler abnormalities associated with impaired LV relaxation [17]. This is known as pseudonormalisation. Pulmonary venous flow profiles provide important complementary information, when they are recorded simultaneously and help to differentiate the E:A (E=early filling, A=atrial filling) pattern from that of a normal person.

Despite the limitations of Doppler-echocardiography, it has emerged as the best non-invasive method of diagnosing diastolic dysfunction in routine clinical settings. There is, however, an ongoing discussion over which echocardiographic variable, should be used for evaluating diastolic function in the broader routine clinical setting.

1.1. Study rationale
The rationale for this study was based on the hypothesis that carvedilol's pharmacologic profile, combining non-selective beta-receptor blockade and selective vasodilating alpha-1 receptor blockade, might be of special value in DHF through its hemodynamic and functional effects on LV remodelling. Beta-receptor blockade has been shown to improve relaxation and DF [18] and to improve ischemia [19], but specific studies in patients with DHF are lacking.

1.2. Objectives
The aim of the study was to investigate the effects of carvedilol as an addition to conventional treatment (e.g. diuretics and/or ACE-inhibitors and/or digoxin) on DF in patients with HF with preserved systolic function and evidence of diastolic dysfunction determined by Doppler echocardiography.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 References
 
2.1. Study population
The study was a prospective, randomised, double-blind, placebo-controlled, multi-centre study (Fig. 1). One hundred and forty three patients were screened but 30 did not meet the inclusion criteria. Thus 113 patients with symptoms and/or signs of HF, normal or almost normal systolic function and abnormal DF who did not have a contraindication to receiving therapy with a beta-adrenoceptor blocking agent were included into the study.


Figure 1
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  		Fig. 1 Study design. U-T=up titration period. D-T=down titration period.

 
The study was approved by the Ethics Committee of Linköping University and by all other Ethics Committees from the institutions involved in the trial. The nature and purpose of the investigation were carefully explained to the patients, who gave their written informed consent. The study was conducted according to Good Clinical Practice and the Declaration of Helsinki.

Major inclusion criteria were a wall motion index (WMI)≤1.2, i.e akinesia of one segment or less or hypokinesia of 2 segments or less, using a 16 segment model with at least 10 segments visible, corresponding to an LVEF >45% [20], and evidence of abnormal DF using at least one of the following criteria to assess diastolic dysfunction (Table 1) [16,22];

  1. E:A ratio lower than age-related reference value,
  2. Isovolumic relaxation time (IVRT) longer than age-related reference value, and
  3. Normal E:A ratio together with either
    1. pulmonary vein systolic/diastolic velocity (pv S/D) less than normal age-related value,
    2. pulmonary vein atrial reversal duration greater than mitral atrial duration (mitral a dur.) by greater than 20 ms, or
    3. pulmonary vein atrial reversal velocity is greater than normal age-related value.


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  		Table 1 Cut-off values for diastolic dysfunction for different age groups (Refs. [16,22])

 
Major exclusion criteria were restrictive or hypertrophic cardiomyopathies, significant uncorrected obstructive or regurgitant valvular diseases, unstable angina, active myocarditis, uncontrolled symptomatic ventricular arrhythmias, history of sick sinus syndrome, second or third degree AV-block, heart rate less than 60 bpm, systolic blood pressure <85 mmHg, uncontrolled hypertension, atrial fibrillation, evidence of obstructive pulmonary disease, unstable diabetes, treatment with beta-2-agonists, MAO-inhibitors, calcium channel blockers or beta-receptor blockers.

2.2. Study endpoints
The primary endpoint of the study was the regression of diastolic LV dysfunction measured by Doppler echocardiography as defined by an improvement in DF determined by changes in mitral doppler flow profiles, IVRT, E:A ratio and pulmonary flow velocities. This primary endpoint was assessed by a composite semiquantitative endpoint including measurable changes of all four Doppler variables of DF from baseline to follow-up. The four variables were change of: E:A ratio, mitral atrial (a)-wave duration compared to pulmonary venous atrial duration, IVRT, and pv S/D. The limits used as ‘measurable changes’ of diastolic variables constituting the primary endpoint were prospectively defined as follows: E:A ratio >0.15; E-deceleration time >20 ms; IVRT >10 ms; pv-S/D >0.2. The changes in the patient's DF were calculated by assigning a score to each one of the four variables: +1 for improvement, 0 for no change and –1 for worsening. All values of the four variables for each patient were added up, positive sums being regarded as ‘improvement’, zero as ‘no change’ and negative sums as ‘worsening of the overall diastolic function’. Secondary endpoints were the effects of carvedilol as compared to placebo on combined all cause mortality and cardiovascular hospitalisations, combined all-cause mortality and heart failure hospitalisation, progression of heart failure, individual cardiovascular endpoints and outcome and individual diastolic variables. Additional exploratory analyses on LV dimensions atrial size and WMI were also prespecified.

2.3. BNP-analysis
Blood samples for analysis of BNP were drawn while the patient was fasting and resting in the supine position. Plasma BNP was analysed using a direct and specific immunoradiometric assay for human BNP (Shionoria).

2.4. Study phases
The study consisted of 4 phases (Fig. 1). Patients satisfying the inclusion and exclusion criteria were assigned to carvedilol or placebo twice daily in addition to their conventional treatment by 1:1 randomisation.

All patients were uptitrated to the maximum tolerated dose or to the target dose (25 mg b.i.d., or 50 mg b.i.d. in patients weighing >85 kg) of carvedilol or matching placebo. After completion of uptitration they were to continue on double blind medication for a 6 month maintenance period. At study end patients were withdrawn from blinded study medication in a stepwise manner over a 1–3 week period. Optimal therapy for the patient's condition was then reinstated at the investigator's discretion.

2.5. Doppler-echocardiography
Two-dimensional and Doppler echocardiographic examinations were performed at baseline and at the end of the maintenance phase or in case of early withdrawal. For the purposes of inclusion, all baseline echocardiograms were sent to the echocardiography core laboratory.

2.5.1. Two-dimensional echocardiography
The WMI was evaluated at baseline and was repeated at the end of the 6 month maintenance phase or in case of early withdrawal. The 16-segment model for assessing LV wall motion was evaluated in the 5 standard projections [20] and assigned following the standard semiquantitative scoring system (1-normal, 2-hypokinesis, 3-akinesis, 4-dyskinesis, 5-aneurysm). The WMI was calculated by dividing the number of rated segments by the number of visualized segments [20].

LV end-diastolic diameter, LV end-systolic diameter, LV wall thickness and left atrial size were acquired according to recommendations of The American Society of Echocardiography [21]. Each measurement was determined by averaging 3–5 consecutive measurements.

2.5.2. Doppler-echocardiography
All Doppler-echocardiographic assessments were acquired according to the recommendations of the American Society of Echocardiography [20]. The transmitral flow was recorded from the apical four-chamber view with the pulsed Doppler sample volume placed at the tips of the mitral leaflet during diastole. The following variables were assessed from transmitral flow: E wave velocity, A wave velocity, E:A ratio, A wave duration, E deceleration time, IVRT. IVRT was measured as the interval between aortic valve closure and the onset of mitral flow.

The velocity of the pulmonary venous flow was obtained from the apical window with the sample volume immediately proximal to the orifice of the right pulmonary veins at the roof of the left atrium and the following variables were measured: systolic velocity, diastolic velocity, A-velocity, A-duration.

All assessments as to whether the LV diastolic dysfunction had improved, was unchanged, or had worsened were made by two echocardiographers from the core laboratory, who were blinded to the order of the assessment and to the study medication received by the patient. The initial evaluation was performed in a random order without knowledge of the date of the examination or the heart rate. Prior to evaluation, all tapes were assessed for satisfactory quality of the recordings.

2.6. Statistics
Assuming an improvement in DF in <10% of patients randomised to placebo, 67 patients per treatment arm were calculated to be sufficient to detect a difference of at least 25% between the groups. Continuous efficacy variables are expressed as mean and S.D. Categorical data are presented in percentages. All statistical analyses were two-sided. Analysis of interactions were considered significant at a value of P<0.01. All other analyses were considered significant at a value of P<0.05.

The Cochran–Armitage trend test was used in the analysis of the primary efficacy variable and E:A ratio and other diastolic function variables changes from baseline to end of maintenance. Analysis of variance was used to assess the other continuous secondary efficacy variables.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Appendix A
 References
 
3.1. Study population
Of the 113 patients randomised to study treatment at 12 different hospitals in Sweden, 16 patients had echocardiographic data of insufficient quality and were excluded from the evaluation. Thus 97 patients completed the study and were analysed on the basis of intention to treat, 95 of whom completed the whole study period. Basal characteristics of the patients are shown in Table 2.


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  		Table 2 Baseline characteristics

 
Prior to randomisation the majority of the patients (n=81) were receiving medication for cardiovascular diseases, mostly furosemide, enalapril and aspirin.

No patient died during the study. Overall, 12 patients (six in the carvedilol and six in the placebo group) were hospitalised for periods of between one and 8 days, during the study period. Six patients were hospitalised for cardiovascular reasons; four in the carvedilol group (two worsening heart failure and two chest pain) and two in the placebo group (two chest pain).

Overall, carvedilol was well tolerated, with 81% of patients receiving the maximum dose at the end of the uptitration phase (25 mg b.i.d. or 50 mg b.i.d.) and 82% at the end of the study. All patients randomised to placebo were on the maximum dose at the end of the study.

3.2. Doppler-echocardiography
The most common feature of diastolic dysfunction measured at entry was an E:A ratio lower than the age-adjusted reference value [16,22] in 81 patients (84%). The IVRT was longer than the age-adjusted reference value in 14 (14%) patients while pulmonary venous flow was abnormal in only two patients (2%) (Table 2). The composite primary endpoint showed improvement of DF in 51% of the patients treated with carvedilol compared to 40% of those receiving placebo, remained unchanged in 19% (carvedilol) compared to 22% (placebo) and worsened in 30% of patients treated with carvedilol compared to 38% of those receiving placebo (Table 3). No statistically significant difference was found between the groups for the composite primary endpoint.


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  		Table 3 Change in diastolic dysfunction from baseline to month 6. Number of patients (%)

 
When individual diastolic variables were considered, there was a significant increase in age-adjusted E:A ratio in the carvedilol treated patients at the end of the study (P=0.046) but no significant changes in DT or IVRT or pv S/D (Table 4).


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  		Table 4 Changes in individual diastolic characteristics before and after 6 months of treatment. P-value refers to treatment group differences

 
3.2.1. Effects related to baseline heart rate
Doppler data were also analysed according to baseline heart rate in the two treatment groups. In this analysis a significant relation between treatment effect and baseline heart rate was found. Patients with a higher baseline heart rate (above the median value of 71 bpm) clearly responded better to carvedilol, as compared with patients with lower heart rate (Fig. 2a,b). There were no differences between the carvedilol and placebo group in patients with lower heart rates. Further, in the primary endpoint evaluation of diastolic function, there was a trend towards a better effect in patients with higher heart rate, although this was not statistically significant (Fig. 3a,b).


Figure 2
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  		Fig. 2 Changes in E:A ratio in relation to baseline heart rate. Patients with heart rate above 71 bpm had a significant increase in E/A ratio and E wave velocity, and a decrease in A wave velocity when treated with carvedilol.

 


Figure 3
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  		Fig. 3 Changes in the composite primary end-point (see text for definition) during the study period in relation to baseline heart rate. Patients with heart rate above 71 bpm had a significant increase in E/A ratio and E wave velocity, and a decrease in A wave velocity when treated with carvedilol.

 
3.3. Two-dimensional echocardiography
No significant differences were found at the end of the study regarding LV volumes and systolic function except for left atrial size (P<0.05) (Table 5).


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  		Table 5 Left ventricular systolic measurements and BNP-values before and after treatment with carvedilol or placebo for 6 months. P-value refers to treatment group differences

 
3.4. Heart rate, blood pressure and symptoms
Heart rate was unchanged in the placebo group (73 bpm at baseline, 72 bpm at the end of the study), and decreased in the carvedilol group (74 bpm and 60 bpm, respectively, P<0.0001). The difference in the absolute change between the placebo and the carvedilol group was statistically significant (P<0.0001). No significant change in systolic or diastolic blood pressure was found during the study between the two treatment groups.

At the end of the study, 30 patients in the placebo group and 31 in the carvedilol group showed no change in NYHA class. Improvement was described in 12 patients (placebo) compared to two (carvedilol). There was a deterioration of NYHA class in eight (placebo) compared to 14 (carvedilol) patients (differences not statistically significant).

Regarding patient's global assessment of symptoms, about one third of the patients in both groups reported an overall improvement of symptoms at the end of the study. Slightly more than half of the patients did not report a change in symptoms.

3.5. Adverse effects
The frequency and type of adverse effects were similar in both groups, the most frequent being dizziness (12%), dyspnoea (7%), asthenia (6%) and headache (5%). There were no significant changes in clinical laboratory data in the two groups during the study.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Appendix A
 References
 
To date, few randomised, placebo-controlled studies in patients with DHF have been published, and these have included a limited number of patients over a relatively short period of time [23,24]. The present study is the first double-blind, placebo-controlled study with a beta-blocking agent, to attempt to include a sufficient number of patients with DHF followed-up for a reasonably long period of time. Of the individual diastolic variables chosen to assess diastolic dysfunction, only the E:A ratio showed a statistically significant difference (P=0.046) in favour of carvedilol at the end of the study. In contrast, the composite primary endpoint showed no statistically significant difference between the two treatment groups. However, less than 20% of the included patients had any age-adjusted abnormal DT, IVRT and pv S/D at baseline, probably making it more difficult to show a pharmacological effect on mostly normal values. Moreover, and as expected, treatment with carvedilol resulted in a significant decrease in heart rate and the response on time-related variables (IVRT and DT) could have been blunted by the reduction of heart rate induced by carvedilol.

Although the heart rate effect could be an explanation for the improvement in DF seen with carvedilol, the same heart rate might also preclude a proper interpretation of the results on these time-related variables and its comparison with the placebo group. By significantly reducing heart rate, carvedilol allows more time for the diastolic filling of the heart. In a previously published study [25], carvedilol restored physiologic early diastolic filling by complex interactions between relaxation and chamber stiffness.

These findings, added to the versatility of recording E and A velocities compared to other variables of diastolic dysfunction, make the E:A ratio likely to be the most robust non-invasive variable to assess patients with relaxation abnormalities who are being treated with a beta-blocker.

4.1. Definition of diastolic dysfunction
The chosen Doppler-echocardiographic variables and reference values to assess diastolic dysfunction in the present study were based on publications from the mid 1990s [26,27]. At that time there were no published guidelines regarding how to define DHF.

The current recommendations by the European Study Group on DHF [6] are in some aspects based on the use of more strict values to define diastolic dysfunction. However, the European guidelines have not yet gained general acceptance. However, in the recently published guidelines from ACC/AHA [28] the term ‘HF with preserved systolic function’ was introduced making it no longer mandatory to objectively assess DF in these patients. Accordingly, today there is no worldwide accepted definition of DHF. Moreover, in a recent paper published by Cahill and co-workers [29] investigating patients admitted to hospital with a primary diagnosis of HF, confirmed by clinical symptoms and signs, radiographic evidence of HF and clinical response to diuretic therapy, of the 99 patients with preserved systolic function (mean EF 55%) and no significant heart valve disease, only 43% met the inclusion criteria for DHF as recommended in the European guidelines [6]. Using IVRT alone, 41% would be classified as DHF. Using the E:A and DT indices of slow early diastolic filling, this proportion would fall to 7%. One may therefore question whether the European guidelines are sensitive enough to diagnose patients with DHF using non-invasive means. However, Jarnert et al. [30] reported that Doppler tissue imaging and transmitral Doppler flow variables had a similar diagnostic accuracy for DHF and were superior compared to the method of atrio-ventricular plane displacement. Thus, more sensitive, reproducible methods are needed to diagnose DHF non-invasively.

4.2. Change in NYHA-class, atrial size, BNP and patient population
The trend towards a deterioration in NYHA class in patients treated with carvedilol was an unexpected finding, but is most likely explained by the adverse effects of beta-blockade. Similar findings were found regarding atrial size and plasma BNP levels, again this can probably be explained by the treatment with carvedilol. Subjective evidence of symptomatic improvement would have been impossible to assess in those patients who were classified as NYHA class I. Indeed, while all patients complained at least of exertional dyspnoea, in about one third of these patients, investigators interpreted their symptoms as being ‘normal’ and classified the patients as being in NYHA class I. There was additionally an imbalance in the randomisation of patients classified as NYHA class I at baseline, with 26% of these patients randomised to placebo, and 40% randomised to carvedilol, which is a clinically important difference.

4.3. Treatment effects by carvedilol
A short diastolic period is always detrimental if myocardial function is compromised. Beta-blockers prolong the diastolic period more than they prolong the systolic period, which promotes diastolic filling and improves myocardial perfusion and metabolism [19]. It is not likely that carvedilol treatment is associated with improvement in myocardial relaxation velocity, but rather a slower rate of rapid filling. Nevertheless, filling is shifted from late to early diastole, and, therefore induces a more normal filling pattern [18]. It is difficult to differentiate the effects on heart rate per se from other beta-blocking effects. However, there are several indications that the mode of action of beta-blockade is not solely through heart rate reduction. Other drugs with heart rate reducing effects, e.g. calcium channel blockers and digitalis, do not share the positive effects of beta-blockers in HF treatment.

When effects of treatment were related to baseline heart rate, it was obvious that patients with higher heart rates benefited more from carvedilol treatment than did patients with lower heart rates. Patients on carvedilol with heart rate above 71 bpm responded with an improvement in E:A as well as in E-wave velocity, whereas there was less effect on the A-wave velocity in comparison with the placebo group. These findings support the theory that patients with diastolic dysfunction and higher heart rates improve diastolic filling through a shift of diastolic volumes from late to early diastole. It appears that this redistribution of filling volumes towards a more normal pattern is brought about by an improvement in early filling in particular.

4.4. Study limitations
Sample size: Although it was calculated that 134 patients were required to show a significant treatment effect at the end of the study period, only 70% of the original sample size was evaluable.

Severity, assessment and characteristics of diastolic dysfunction: In 2/3 of the patients, the underlying reason for diastolic dysfunction was hypertension, with 95 patients presenting with a relaxation abnormality and probably slightly elevated filling pressures. In only two patients (one in each group) was a pseudonormalised pattern evident. Thus the degree of diastolic dysfunction was milder than expected in our study. While IVRT or DT has been suggested to be the most appropriate variable to assess DF [31], in our study IVRT and DT were normal in some 80% of the patients compared to the age-adjusted reference values. Further, a proper interpretation of the composite primary endpoint included several variables, including registration of pulmonary venous flow, which is often difficult to obtain with high quality recordings. Heart rate of 71 bpm at rest is, however, not a very high heart rate, and, therefore patients with this characteristic could readily be identified in a clinical setting.

It is well known that clinical symptoms and signs of heart failure are unspecific and may cause misdiagnosis. However, we tried to avoid misdiagnosis by including an objective measure of diastolic dysfunction in accordance with current criteria for heart failure.


   5. Conclusion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Appendix A
 References
 
This study is the first controlled trial with a beta-blocking agent to assess DHF with a sufficient number of patients. The results show that treatment with carvedilol produced some evidence of an improvement in DF compared to placebo in patients with DHF and relaxation abnormality, in particular in patients with higher heart rates. The E:A ratio was the most useful variable to identify the improvement in DF in this patient population.


   Appendix A
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
References
 
Steering committee: U. Dahlström, E. Nylander, B. Andersson, H. Persson, M. Edner.

Investigators: U. Dahlström, E. Nylander, Linköping (35); P. Ahlström, Motala [4]; A. Bergström, Jönköping [3]; F. Landgren, Kalmar [2]; L. Falk, Mölndal [9]; B. Andersson, Göteborg [8]; H. Persson, M. Edner, Danderyd [16]; C. Höglund Stockholm HC [3]; B. Samad Stockholm (SÖS) [2]; K. Boman, Skellefteå [11]; P. Lövdahl, Helsingborg [11]; P. Kvidal, B. Andrén, Uppsala [9].


   Acknowledgements
 
The authors would like to thank Christine Moullet, MD and Armin Scherhag MD, F. Hoffmann-La Roche Ltd for invaluable help and support during the study. The study was investigator-initiated and was partly funded by F. Hoffmann-La Roche Ltd.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 References
 
{star} For the SWEDIC investigators are listed in Appendix A. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A
 References
 

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