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European Journal of Heart Failure 2005 7(4):604-611; doi:10.1016/j.ejheart.2004.03.008
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© 2005 European Society of Cardiology

Effects of bisoprolol treatment for chronic heart failure initiated and followed up by primary care physicians

A. Schuchert* and On behalf of the BISEX Investigators (Appendix A)

Medical Clinic III, University-Hospital Hamburg-Eppendorf Martinistr. 52, D-20246 Hamburg, Germany

* Tel.: +49-40-428035304; Fax: +49-40-428035766. E-mail address: schuchert{at}uke.uni-hamburg.de


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. BISEX (Bisoprolol...
 References
 
Primary care physicians prescribe beta-blockers for chronic heart failure infrequently. The aims of the study were to assess the effects of beta-blocker treatment in out-clinic patients with regard to NYHA class and frequency of adverse events. Beta-blocker treatment was initiated and followed up by primary care physicians.

Methods: Chronic heart failure patients already treated with ACE-inhibitors and diuretics were included. The 24-week follow-up consisted of a titration phase followed by a maintenance phase. The patients received the beta-blocker bisoprolol with an initial dose of 1.25 mg and a maximal dose of 10 mg.

Results: NYHA class II, III and IV had 174, 146, and one patient, respectively. Treatment duration lasted 189±73 days with a maximal bisoprolol dose of 7.2±3.2 mg. Sixty-one percent of the patients tolerated at least 7.5 mg bisoprolol. The NYHA class improved from 2.4±0.5 at baseline to 1.8±0.6 at week 24 (P<0.001). At final assessment, 74% of the patients showed an improvement. The number of permanent treatment withdrawals was 57 (17%). Death occurred in six patients and hospitalisation in 38 patients.

Conclusions: Bisoprolol treatment in patients with chronic heart failure was effectively and safely carried out by primary care physicians.

Key Words: Chronic heart failure • Adrenergic beta-antagonists • Bisoprolol • Heart rate • Blood pressure • NYHA class

Received September 12, 2003; Revised January 12, 2004; Accepted March 29, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. BISEX (Bisoprolol...
 References
 
Chronic heart failure is an emerging epidemic, one of the leading causes of hospitalisation in older people, and has become an increasing health problem [1–3]. Medical treatment for heart failure has improved during the last decade [4]. Keystones in the medical treatment of heart failure are ACE-inhibitors and beta-blockers. Today the prescription of ACE-inhibitors seems to be well established in these patients [5,6].

Beta-blocker therapy, used in conjunction with ACE-inhibitors and diuretics, has been shown to lessen heart failure symptoms and improve NYHA functional class in patients with systolic dysfunction [7,8]. Randomised double-blinded trials published since 1999 also demonstrate an improved survival compared to placebo [9–12]. As a consequence, European and American guidelines for the treatment of chronic heart failure were updated in 2001. At present, beta-blockers are a class I drug for the medical treatment of chronic heart failure [13,14].

Despite these well-established benefits, primary care physicians only infrequently prescribe beta-blockers for chronic heart failure or do not give them at the target dose level [5,15,16]. The differences between the guideline recommendations and real life do not seem to be related to a lack of awareness or perception [5]. However, most physicians who contributed patients to the randomised beta-blocker trials worked in teaching hospitals and had broad experience in the management of heart failure patients. Primary care physicians do not have the same level of experience in treating heart failure patients. In case of adverse events, primary care physicians could be more likely to withdraw the beta-blocker earlier or to maintain it at low dose levels. It is an issue to demonstrate that primary care physicians can initiate beta-blocker treatment in heart failure patients with equal efficacy to published randomised trials [9–12].

The aims of this prospective study were to investigate the effects of beta-blocker treatment in out-clinic patients with regard to functional NYHA class, heart rate and blood pressure as well as frequency of adverse events. The treatment was initiated and followed up by primary care physicians.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 Appendix A. BISEX (Bisoprolol...
 References
 
2.1. Patients
Patients aged from 18 to 80 years with stable chronic heart failure and depressed left ventricular function were included in this prospective study. Patients had to have a history of heart failure for at least the preceding 6 weeks on basic therapy consisting of ACE-inhibitors or angiotensin-receptor blockers, diuretics and optionally digitalis. The medication had to be unchanged for at least the preceding 2 weeks.

Exclusion criteria were acute or decompensated cardiac failure, obstructive or restrictive cardiomyopathy or myocarditis, myocardial infarction or unstable angina within the last 3 months, congenital cardiac disease, hemodynamically relevant valvular heart disease, PTCA or CABG planned or carried out within 6 months, heart transplantation carried out or planned, bradycardia below 60 beats per min or AV-block II or III or sick sinus syndrome without pacemaker prior to treatment, stroke within the last 12 months prior to the start of the study, systolic blood pressure <100 mmHg, restrictive pulmonary disease, cor pulmonale or bronchospasm, psoriasis in the medical history or family history, significant renal impairment, poorly controlled diabetes mellitus, known contra-indications for beta-blockers or bisoprolol, pregnancy or lactation period, need for non-permitted concomitant medication (other than beta-blockers, inotropic agents except for digitalis, ergotamine derivatives, calcium antagonists (including verapamil), clonidine, MAO-inhibitors except for MAO-B, antiarrhythmics except for amiodarone).

Informed consent was obtained from all patients. The study was conducted in accordance with the current version of the Declaration of Helsinki and the CPM/ICH/135/95 guideline. The trial protocol was approved by an independent ethics committee and by local committees.

2.2. Study protocol
The study consisted of a titration phase followed by a maintenance phase. The total study duration was 24 weeks. All patients received the ß1-selective adrenoceptor blocker bisoprolol (Concor, Merck KGaA, Germany) with an initial dose of 1.25 mg. The recommended maximal dose was 10 mg once daily. The dose schedule for up-titration of the beta-blocker was 2.5 mg after week 1, 3.75 after week 2, 5 mg after week 3, 7.5 mg after week 7, and 10 mg after week 11.

This titration schedule was to be adhered to as long as there were no signs of intolerance. Any reductions of the bisoprolol dose had to be made step by step. Likewise, bisoprolol treatment was not to be stopped abruptly, but by halving the dose at weekly intervals. Investigators were to consider dose reductions particularly in the event of bradycardia (heart rate<60 bpm), hypotension (<100 mmHg), syncope, fatigue or orthostatic dizziness. If bisoprolol therapy was discontinued for more than 2 weeks and would therefore have to be resumed at a lower dose level, the study was to be terminated in the respective case.

The primary endpoint was change in NYHA class at the end of treatment compared with the baseline visit. Secondary efficacy variables were changes at 7, 19 and 24 weeks, vs. baseline, in NYHA class as well as the investigators’ assessments of changes in heart failure symptoms compared with baseline, using the three categories: improved, unchanged, worsened. The effect of beta-blocker treatment was also investigated with regard to changes in heart rate and blood pressure as well as frequency of permanent treatment withdrawals, adverse events resulting in hospitalisations and death.

Measurements of systolic and diastolic blood pressure as well as heart rate were performed at every visit. Blood pressure was measured with a sphygmomanometer in the sitting position after 5 min of rest. The NYHA class was determined at baseline as well as at 7, 19 and 24 weeks after initiation of the treatment. At the same time investigators were asked to describe whether heart failure symptoms had generally improved, worsened or remained unchanged. Frequency and causes of hospitalisation were determined.

2.3. Statistical methods
For ordinal data the homogeneity of the marginal distributions (i.e. the identity of the distributions at baseline and a specific follow-up assessment) was tested using Cochran–Mantel–Haenszel statistics. The symmetry of the changes was tested using the symmetry test of Bowker. For all tests the significance level was set at 0.05, two-sided.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 Appendix A. BISEX (Bisoprolol...
 References
 
3.1. Patients
From September 1999 to May 2000, 184 German primary care physicians included 328 patients with a mean age of 63±10 years of whom 222 (68%) were male. Body height was 170±9 cm and body weight 80±14 kg. Frequent non-cardiovascular co-morbidities were diabetes in 69 (21%) patients, lipoid metabolism disorders in 83 (25%) patients, and thyroid disorders in 18 (5.5%) patients. Concomitant medication consisted of diuretics and ACE-inhibitors in all patients. Instead of ACE-inhibitors 16 patients received angiotensin-receptor blockers. Cardiac glycosides were prescribed in 180 (55%) patients, digoxin in 95 cases and digitoxin in 85 cases. The cardiac rhythm on the baseline ECG was sinus rhythm in 262 (80%), atrial fibrillation in 50 (15%), and a pacemaker rhythm in 15 (5%) patients. One hundred seventy-four patients were in NYHA class II, 145 in class III, and one patient in class IV. Heart failure was of ischemic origin in 122 patients (37%) including 55 patients with a history of bypass surgery. One hundred fifty-six (48%) patients had a history of arterial hypertension.

The mean treatment duration was 189±73 days including the time up to the maximal dose of 65±41 days. The maximal beta-blocker dose was 7.20±3.15 mg. Fig. 1 shows the distribution of the maximal prescribed dose level ranging from 1.25 to 10 mg. Sixty-one percent of the patients received at least 7.5 mg bisoprolol during the study.


Figure 1
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  		Fig. 1 Distribution of the maximally tolerated bisoprolol dose level.

 
3.2. NYHA class and heart failure symptoms
At baseline, the mean NYHA class was 2.4±0.5. The NYHA functional class significantly improved from baseline up to the earliest re-assessment at week 7, to 2.0±0.6 (P<0.001), at week 19 to 1.8±0.6 (P<0.001), and at week 24 to 1.8±0.6 (P<0.001). The distribution of the four NYHA classes is depicted in Fig. 2.


Figure 2
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  		Fig. 2 Distribution of NYHA classes at baseline and during follow-up.

 
At the earliest re-assessment many patients reported an improvement which was maintained throughout the study until the final follow-up visit (Fig. 3a). At final assessment, 74% of the patients showed an improvement, 21% no change, and 5% a worsening. A significantly better improvement was seen for patients in NYHA class III at baseline compared to the patients in NYHA class II at baseline (P<0.0001) (Fig. 3b).


Figure 3
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  		Fig. 3 (a) Changes in heart failure symptoms at follow-up visits. (b) The final visit revealed a significantly better improvement of patients in NYHA class III at baseline compared to patients in NYHA class II.

 
3.3. Heart rate and blood pressure
Before beta-blocker treatment, the heart rate at rest was 80±13 beats per min. Within one week after initiation of beta-blocker treatment, the heart rate decreased significantly by –7.7±11.6 beats per min (P<0.0001). The mean decrease in heart rate after 24 weeks was –14.5±13.9 beats per min (P<0.0001) (Fig. 4a).


Figure 4
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  		Fig. 4 (a) Decrease in heart rate after initiation of beta-blocker treatment. (b) Decrease in systolic blood pressure after initiation of beta-blocker treatment.

 
At the start of the study, systolic blood pressure was 136±19 mmHg and diastolic blood pressure 81±10 mmHg. After one week of treatment, the systolic value had significantly decreased by –5.8±16.8 mmHg and the diastolic value by –3.3±10.0 mmHg (P<0.0001). After 24 weeks, systolic blood pressure decreased by –9.1±19.3 mmHg and diastolic blood pressure by –4.5±11.4 mmHg (P<0.0001; Fig. 4b; Table 1).


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  		Table 1 Decrease in diastolic blood pressure

 
3.4. Adverse effects
Beta-blocker treatment was permanently withdrawn in 57 (17%) patients. The reasons for treatment withdrawal were adverse events in 40 cases, lost to follow-up in six, withdrawal of consent in five, protocol violation in three, and other reasons in three cases. The frequency of adverse events within the first 8 weeks after initiation of treatment (23 cases (7.0%)) was similar to the number of events in the time interval after 8 weeks (17 cases (9.4%)).

Six patients experienced serious adverse events leading to death with four cardiac (sudden cardiac death n=3) and two non-cardiac deaths (intracerebral hemorrhage n=1; esophagus carcinoma n=1). Adverse events leading to at least one hospitalisation were reported in 38 patients. No patient had a symptomatic bradycardia with the indication for a permanent cardiac pacemaker.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
Appendix A. BISEX (Bisoprolol...
 References
 
The treatment with bisoprolol in patients with chronic heart failure was effectively and safely carried out by primary care physicians. At baseline the patients were either in NYHA class II or III despite their medical treatment consisting of ACE-inhibitors and diuretics and, in 52% of cases, digitalis. After adding bisoprolol to their pre-existing beta-blocker-free therapy most patients improved their NYHA class and heart failure symptoms. Most of the patients tolerated the treatment with bisoprolol well.

4.1. Patients
The type of β1-selective adrenoceptor blocker and the titration schedule used in the present study were related to the CIBIS II trial [9]. The main purpose of the present study was not to replicate the randomised double-blinded placebo-controlled CIBIS II trial, but to assess whether this approach of beta-blocker treatment is feasible in the setting of primary care physicians. Therefore, one of the differences between the two trials was that in the present study, primary care physicians initiated the treatment and followed up the patients and not physicians from teaching hospitals, as in the CIBIS II trial. Other differences were the lack of a placebo group and a limited follow-up over 24 weeks. Since randomised trials have demonstrated the efficacy of beta-blocker treatment in patients with chronic heart failure, it is no longer justified to withhold beta-blockers from some patients so that they can serve as controls. The follow-up was limited to 24 weeks because titration to the maximal tolerable dose level seems to be a critical part in beta-blocker treatment [17,18].

The distribution of clinical data obtained in the present study was similar to the CIBIS II trial, e.g. age, prescription of digitalis, origin of the heart failure, and frequency of atrial fibrillation. Differences between the two studies were, higher percentages of male (CIBIS II 81%) and of NYHA class III patients (CIBIS II 83%) in the CIBIS II trial [9]. In respect to the distribution of the NYHA functional classes, our study was more similar to the MERIT-HF trial [10].

4.2. Maximal bisoprolol dose level
The primary care physicians followed the recommended titration schedule in the vast majority of cases and 47% of the patients reached the maximal dose of 10 mg bisoprolol once daily. In the CIBIS II trial, 43% of the patients received 10 mg bisoprolol, 11% 7.5 mg, and 13% 5.0 mg bisoprolol during the maintenance phase [9]. In a recent post-hoc analysis of the CIBIS II data, bisoprolol reduced mortality in heart failure patients at all tolerated dose levels [19].

The present study demonstrated the feasibility of primary care physicians safely initiating beta-blocker treatment in heart failure patients and achieving the recommended target dose in many patients under routine conditions. A limitation of the present finding is that it was a controlled study with documented follow-up visits. In a recent survey among primary care physicians only about a fifth of patients taking beta-blockers had this treatment initiated from primary care [5]. Moreover, the doses prescribed were approximately 50% of the target doses suggested by the ESC guidelines [5]. In a more recent survey among hospitals, more patients received beta-blockers but the daily dosage of beta-blockers was far below the target doses used in randomised studies [6].

4.3. NYHA class improvement
At the final visit, 55% of the patients had improved by one or two NYHA classes. The CIBIS II, MERIT HF, CORPERNICUS and COMET trials primarily assessed the effects of beta-blocker treatment on mortality and morbidity [9–11]. Symptomatic improvement after the initiation of beta-blocker treatment was assessed in other studies [7,8]. In the present study, with regard to both NYHA class and description of heart failure symptoms, many patients had improved at the earliest follow-up, even before reaching the optimal dose. This may indicate that the initiation of this beta-blocker seems not to be associated with an intermittent symptomatic worsening [17].

4.4. Heart rate and blood pressure
Beta-blockers reversibly bind with beta-adrenergic receptors to block the response to sympathetic nerve impulses or catecholamines. Long-term treatment with beta-blockers prevents the inadvertent effects of prolonged elevated sympathetic activation often seen in chronic heart failure. As an obvious vital sign, heart rate decreases after initiation of beta-blocker treatment and patients with a decrease in heart rate have a better prognosis compared to the remaining patients [20]. The mean heart rate in the present study decreased by –14.5±13.9 beats per min at the final visit. In the two CIBIS trials, the heart rate decreased by –16.3±15.3 and by –9.8±14.7 beats per min after 2 months each, and in the MERIT-HF trial by –14 beats per min after 6 months [10,20,21].

The systolic and diastolic blood pressures were significantly reduced in the present study by –5.6±17.6 mmHg and –3.5±10.8 mmHg, respectively. Similar reductions were observed after 2 months in the CIBIS trial with –2.7±17.9 mmHg and –2.7±10.7 mmHg, as well as in the CIBIS II trial with –4.1±16.4 mmHg and –2.6±10.7 mmHg for systolic and diastolic blood pressure, respectively [20,21].

4.5. Adverse events
Total permanent treatment withdrawal was 17% and permanent treatment withdrawal due to adverse events 12%. The latter was similar to the findings of the CIBIS II trial with 15%, MERIT HF trial with 13.9%, and COPERNICUS trial with 14.8% [9–11]. In these three trials, permanent treatment withdrawal was similar in the beta-blocker and placebo-treated groups. In contrast to these studies, our follow-up period lasted only 24 weeks. However, the rate of adverse events turned out to be quite low during the period of treatment initiation, when patients are supposed to be particularly prone to symptoms of treatment intolerance. Therefore, the benefits derived from the initiation of bisoprolol treatment in patients with chronic heart failure clearly outweigh the risk of adverse events potentially associated with it.

All-cause annual mortality was 8.8% in bisoprolol-treated patients in the CIBIS II trial and 7.2% in metoprolol-treated patients in the MERIT-HF trial [9,10]. All-cause hospitalisation was 33% in the active-treatment group of the CIBIS II trial. Mortality and hospitalisation were remarkably low in the present study, which can be related to the shorter 24-week follow-up.

The present study demonstrates the feasibility of initiation of bisoprolol treatment in out-clinic patients by primary care physicians. This approach was safe and efficient. Beta-blocker treatment in heart failure patients not only improves and prolongs patients’ lives but also helps to cut costs of health care [22].


   Appendix A. BISEX (Bisoprolol Experience) Investigators
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. BISEX (Bisoprolol...
References
 
Behnan Hägele, Karl-Dieter Gater, Christian Köhler/Coppenrath, Wolfram Ryba, Roland Rackwit, Roland Morell, Karl Schön, Hans Schlüter, Hans Jörg Heidersberger, Hartmut Dobritz, Ernst Birkmeier, Ulrich Brügmann, Wolfgang Paulus, Stefan Wiese, Klaus Vorbeck, Jürgen Essig, D.R. Stöhring, Dietmar Naegle, Michael Nist, Reinhold Wolf, Matthias Zander, Albrecht Dörr, Andreas Hölscher, Seyfettin Dereli, Karl-Friedrich Appel, Andreas Meinel, Walter Engelings, Harald Meißen, Guilleaume Sévère, Norbert Gerich-Düsseldorf, Gamil Qagisc, Jürgen Fritsch, Rainer Heinzler, Ulrich Steinbach, Detlef Bernd Gysan, Christoph Wineken, Ingrid Mitfessel, Martin Diekmann, Rolf Mertens, Andreas Kleemann, Peter Grooterhorst, Konrad Bornikoel, Bernhard Krätzig, Siegfried Frickel, Hans-Ulrich Jötten, Florian Seiler, Gerd-Ulrich Heinz, Wolfgang Burian, Claudia Widenhorn -Müssig, Christian Steenken, Peter Beer, Peter Pinick, Manfred Weingart, G. Jochum, Rainer Häge, Klaus Loskyll, Hans-Jost Schaumann, Manfred Dillschneider, Martina Mertes, Udo Biermann, Andrea Hostert, Eckhard Hermann Wolf, Frank Schwarzbach, Peter Bernhardt, Wolfgang Schmidt, Christian Degenhart, Knut Schmengler, Hans-Joachim Blum, Karl Otto Wirth, Karl-Eugen Hauptmann, Alard Stolte, Christa Link, Manfred Ermisch, Angelika Tägder, Walter Müller, Martin Hinrichsen, Klaus Hofmann, Karl-Heinz Hubold, Uwe Karsten Sauermost, Frank Mittendorff, Ulrich Hageleit, Christoph Naumann d'Alnoncourt, Andreas Maib, Christian Fechtrup, Manfred Hilgedieck, Klaus Rethemeier, Stefan Fromm, Stefan Marcin, Klaus Tamm, Dieter Möllenhoff, Gerhard Ehrentreich, M. Buerschaper, Christian Thelemann, Wolfgang Schallenberg, Gudrun Wisthal, Basem Al-Ghoul, Diehold Schneider, Bernd Schröder, George Bachour, Karl-Georg Furche, Karsten Droese, Eva Westphal, Udo Schwehr, Rüdiger Hahn, Dieter Jänisch-Bernstein, H.-J. Blaschke, Helmut Gekeler, Matthias Redecker, Tarek Dahhan, Thomas André, Susanne Hartmann, Matthias Staiger, Stefan Zieger, Gerhard Merz, Konrad Hein, Bernhard Plappert, Claudia Wankmüller, Jens Otto, Werner Eberle, Elemer v. Czako, Andreas Fuchs, Bernhard Maidhof, Petra Lange-Braun, Helmut Meyer zu Schwabedissen, Larissa Niederstadt, Jens Gramann, Elke Parsi, Rainer Pospiech, Gabriele Haustein, Peter E. Bär, Katharina Brunk, Torsten Ruhnke, Friedrich B. Everling, Michael Wachtarz, Hartwig Schöndube, Gern Semrau, Dieter Gast, Marianne Buhr, Frank Richard, Karl-Heinz Bischoff, Jürgen Frey, Wolfgang Türk, Martin Tietz, Rainer Gräf, Henrik Sachs, Ute Kopplin, Wolfgang Hahn, Gisela Sobeck, Ekkehard Schmidt, Jens Stadtmüller, Michael Funck, Graf von Kageneck, Bernhard Wießmann, Martin Camerer, Helmut Keller, Alexander Noske, Alfred Riedl, Johann Birkel, Klaus Bergmann, Gabi Brütting-Öckl, Anna Savova, Ralf Engelhard, Dagmar Wolff, Frank Schröder, Bernd Krüger, Günter Mahn, Gerhard Heimrich, Wilfried Dänschel, Rainer Lange, Ilona Richter, Joachim Ruh, B. Krosse, Ulla Pilz, Michael Leicht, Ayham Al-Zoebi, Bernd Werner, Uwe Hofmann, Gerhard Hoh, Joachim Gotthardt, Rita Bauer, Michael Schumacher, Burkhardt Friebel, Detlef Götze, Irmtraut Kruck


   Acknowledgements
 
The study was supported by a grant from Merck KGaA.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. BISEX (Bisoprolol...
 References
 

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Eur. Heart J. Suppl., June 1, 2006; 8(suppl_C): C19 - C27.
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