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European Journal of Heart Failure 2004 6(6):761-768; doi:10.1016/j.ejheart.2003.11.025
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© 2004 European Society of Cardiology

Betablockers in heart failure: Carvedilol Safety Assessment (CASA 2-trial)

Hans Ricklia, Simon Steinerb, Karin Müllerc and Otto M. Hessb,*

a Division of Cardiology, St. Gallen Switzerland
b Division of Cardiology, Swiss Cardiovascular Center, University Hospital CH-3010 Bern, Switzerland
c Roche Pharma (Schweiz) AG, Reinach Switzerland

* Corresponding author. Tel.: +41-31-632-96-52; fax: +41-31-632-47-71. E-mail address: otto.martin.hess{at}insel.ch


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Betablockers are a cornerstone in the treatment of patients with chronic heart failure (CHF). The purpose of the present study was to assess safety and tolerability of carvedilol in CHF-patients.

Methods: 66 general practitioners, who were supervised by a local cardiologist, enrolled 151 CHF-patients. All patients were on standard therapy with ACE-inhibitors and diuretics. Carvedilol treatment was started with 3.125 mg twice daily and slowly uptitrated in 2-week intervals to 2x25 mg per day. Mean follow-up was 12 weeks.

Results: 145 of the 151 patients (96%) finished the study according to protocol, six patients were lost to follow-up (4%). 59 patients (41%) experienced minor and nine (6%) serious adverse events. 68 were under maximal therapy with 50 mg daily, 33 received 25 mg, and 15 12.5 mg. Overall tolerability was good and NYHA-class fell significantly from 2.2 to 1.8 (P<0.001). Mean heart rate decreased from 78 to 69 bpm (P<0.001), mean systolic blood pressure from 137 to 132 mmHg (P<0.001) and mean diastolic blood pressure from 80 to 76 mmHg (P<0.001). Quality of life significantly improved under carvedilol with a reduction in the Minnesota living with heart failure score from 1.28 to 0.88 (P<0.001).

Conclusions: Carvedilol is well tolerated in CHF-patients treated by general practitioners. Serious adverse events and hospitalisations are rare. Thus, carvedilol is a safe drug in the treatment of CHF-patients and can be easily initiated and managed by the general practitioner.

Key Words: Chronic heart failure • Carvedilol • Adverse events • Quality of life • Tolerability • General practitioner

Received November 12, 2002; Revised July 18, 2003; Accepted November 12, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
As part of the syndrome of CHF, persistent activation of the neurohumoral system leads to ventricular remodelling and progressive left ventricular (LV) dysfunction [1]. This finally culminates in an increased risk of arrhythmia and sudden death.

Betablockers and ACE-inhibitors are two cornerstones in heart failure therapy. In large multicenter trials these drugs have been shown to reduce mortality and morbidity. In addition, beta-adrenoreceptor blockade often results in a dramatic improvement of LV function and prognosis in patients with both ischemic and non-ischemic aetiology of heart failure [2–6]. Currently, three different betablockers are licensed for the treatment of CHF, namely metoprolol, bisoprolol and carvedilol. Placebo-controlled trials have demonstrated that these betablockers, administered in addition to ACE-inhibitors and diuretics over a period of at least 6 months, have a beneficial effect on cardiac morbidity and mortality, with a reduction in mortality of 30–40%. Furthermore, these compounds lead to a significant improvement in LV ejection fraction and symptoms.

Pharmacological differences between betablockers have been associated with specific effects on haemodynamics and neurohumoral activation. Carvedilol is a non-selective antagonist of beta 1, beta 2 and alpha 1-adrenergic receptors, with an approximately two-fold higher affinity for beta 1 than alpha 1-receptors. In addition carvedilol exerts functions as an antioxidant and free radical scavenger [7-9].

The previous CASA-1 trial (Carvedilol Safety Assessment in Congestive Heart Failure), a multicenter, open-label study, was conducted in order to examine the tolerability and efficacy of carvedilol in addition to standard therapy in patients suffering from moderate to severe heart failure in an outpatient setting [1] The combined therapy of ACE-inhibitors and carvedilol, administered by practising cardiologists, proved to be safe, was well tolerated and showed beneficial effects on ventricular function. The present CASA 2-protocol evaluated similar end-points in a larger number of patients treated with carvedilol in an outpatient setting.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
One hundred and fifty-one patients with stable chronic heart failure NYHA-class II and under standard therapy with an ACE-inhibitor or an angiotensin II-receptor antagonist, digitalis and diuretics (in doses adjusted to achieve clinical euvolemia) were enrolled in this open non-comparative trial.

Informed consent was obtained prior to the conduct of any study-related procedures and independent ethics committee approval was given for all participating centres.

Patients were excluded from the study if they had: myocardial infarction within a month prior to study, uncontrolled hypertension (SBP>160 mmHg or DBP>100 mmHg), unstable angina pectoris in the month preceding study, persistent ventricular arrhythmias, treatment with beta-blockers and alpha-blockers within 2 weeks prior to study start, haemodynamically relevant valvular heart disease, bypass surgery or PTCA within one month prior to study, treatment with diltiazem-like calcium antagonists, verapamil or nifedipine, pheochromocytoma, hyperthyroidism, hypothyroidism, chronic obstructive lung disease or decompensated heart failure of NYHA-class IV.

Further exclusion criteria were: cerebrovascular accident within 3 months prior to study start, cancer or any other serious systemic disease leading to a reduction in life expectancy, renal insufficiency with clinical manifestations, pregnancy, known drug or alcohol abuse, known non-compliance of medications.

Finally, patients were excluded if they had contra-indications to treatment with betablockers or a known hypersensitivity to carvedilol, or did not give written informed consent.

The participating investigators (n=66) were all general practitioners and internists. In the case of clinical problems arising during this open trial, the investigators could contact a designated cardiologist experienced in the use of carvedilol in CHF.

The titration phase started with a dose of 3.125 mg carvedilol twice daily for 2 weeks. Then the daily dose was doubled at 2 week intervals until the maximum tolerated dose (i.e. 2x6.25 mg/day, 2x12.5 mg/day) or the maximum dose of 2x25 mg/day was reached. The maximum tolerated dose was defined as the dose representing best results with regard to efficacy and tolerability. During the titration phase there was a visit every second week, in which heart rate, blood pressure, NYHA-classification, clinical symptomatology, therapy changes, side effects, compliance and information on dosing schedule were examined. The follow-up phase of 4 weeks started when the titration phase was completed with a visit at the beginning and one at the end of the follow-up phase. The maximal duration of the titration and follow-up phases combined was 12 weeks.

Both at the start of the titration phase and in the last visit of the follow-up phase the ‘Minnesota Living with Heart Failure Questionnaire’ (MLwHFQ) was used for the assessment of quality of life. In the MLwHFQ, patients rate 21 questions regarding their quality of life from 0=very good to 5=very bad. The patients’ general condition, as assessed by the investigators at each visit, was divided into: very good—good—moderate—bad—very bad.

The endpoint of the study was the examination of the tolerability of carvedilol treatment in CHF in a general practice setting. This was determined by assessment of minor adverse events, serious adverse events and causes of early termination, assessment of changes in clinical parameters (heart rate, systolic and diastolic blood pressure and NYHA-class), and the assessment of the changes in quality of life with the ‘Minnesota Living with Heart Failure Questionnaire’ as a consequence of treatment with carvedilol.

2.1. Statistics
The safety and tolerability analysis was done on an intention to treat basis, excluding six patients who were lost to follow-up. Efficacy was assessed in patients who tolerated the study medication (n=116). A paired Student's t-test was used to compare the means of paired samples, and Chi-Square-test was used to analyse the contingence tables of different variables at different time points.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
A total of 151 patients were included in the study at 66 out-patient practices, each of them recruiting 1–8 patients. Mean age of the patients was 74.3 (±11.1) years. One patient was 18 years old, the other patients were between 45 and 95 years of age. 40% of the patients were male. Prior cardiovascular events had occurred in 19% of all patients (Table 1).


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  		Table 1 Patient characteristics

 
Of the 151 patients, 145 finished the study according to protocol, six patients were lost to follow-up. 116 of the 145 patients tolerated carvedilol treatment well, 29 patients terminated the study early because of adverse events (n=18), or other reasons (n=11). There were no significant differences between all patients and those who withdrew early from the study (Table 1). Maintenance dose at the end of the study was 50 mg in 58%, 25 mg in 29% and 12.5 mg in 13% of the 116 patients. Mean daily carvedilol doses are listed in Table 2. Concomitant CHF therapy consisted of ACE-inhibitors (74%), AT1 receptor antagonists (15%), diuretics (94%), spironolactone (10%) and digitalis (27%) (Table 3).


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  		Table 2 Changes in heart rate, blood pressure and dose

 


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  		Table 3 Heart failure medication

 
3.1. Haemodynamic changes
Mean heart rate decreased significantly by 10 bpm during the study. Both systolic and diastolic blood pressure decreased significantly by 5–6 mmHg for systolic and 4 mmHg for diastolic pressure, respectively (P<0.001). Fig. 1 depicts the change in heart rate and blood pressure at each visit. The change in heart rate and both systolic and diastolic blood pressure is significantly correlated with carvedilol dosage (P<0.001 for all three parameters) (Table 2).


Figure 1
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  		Fig. 1 Haemodynamics, carvedilol dosage and study withdrawals over time. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure, mean carvedilol dose and withdrawals during carvedilol treatment (from visit 1 to 6). * indicates significant change relative to previous visit (P<0.05).

 
3.2. NYHA classification
Data are reported for the 116 patients who stayed on the carvedilol throughout the study (Fig. 2). At the time of inclusion (visit 1) all patients were in NYHA-class II in accordance with the inclusion criteria. Two weeks after the initiation of treatment with 3.125 mg carvedilol twice daily (visit 2), five patients (3.4%) were in NYHA-class I, 125 (84.4%) in NYHA-class II, 16 (10.9%) in NYHA-class III and two patients (1.4%) in NYHA-class IV. After completion of the titration phase and the 4 week follow-up phase (visit 6), 28 patients (24.1%) were in NYHA-class I, 78 (67.2%) in NYHA-class II, nine (7.7%) in NYHA-class III and one patient (0.9%) in NYHA-class IV (n=116). Mean NYHA-class of the 116 patients was improved significantly (P<0.001) throughout the study.


Figure 2
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  		Fig. 2 NYHA class. NYHA classification in patients on carvedilol (n=116). Bars indicate data at visit 2 (V2) to 6 (V6); P<0.001.

 
Heart failure symptoms were assessed at each visit. The proportion of patients suffering from exercise dyspnoea, pulmonary rales, orthopnoea, nycturia and peripheral oedema decreased significantly for each of these symptoms between baseline and study termination (P<0.001 for each symptom).

3.3. Quality of life
Minnesota Living with Heart Failure Questionnaire (MLwHFQ) was used to assess quality of life (QoL) at the first and the last visit. QoL improved significantly during the treatment period with carvedilol, with a mean score of 1.28 at visit 1 compared to 0.88 at the last visit (P<0.001). The different criteria of QoL in the MLwHFQ varied in the degree of improvement noted after the treatment period. For the following criteria of QoL, a highly significant improvement (P<0.001) was observed:

– Water retention in ankles and legs.
– Impairment of housework and gardening.
– Impairment in activities with family relations.
– Need to sit or lie to recover.
– Fatigue or lack of motivation.
– Impairment of walking or climbing stairs.
– Shortness of breath.
– Insomnia.
– Reluctance to leave home.
– Impairment to perform sports and hobbies.

An improvement with a somewhat lower degree of significance (0.001<P<0.05) was noted for:

– Having to omit favourite meals.
– Poor memory and concentration.
– Sorrow.
– Necessity of hospitalisation.

The remaining criteria showed a tendency to improvement, albeit without statistical significance (difficulty in earning one's living, sexual dysfunction, drug side effects, depression, concern about medical care costs, loss of confidence in life, concern about being a burden for family and friends). The general well-being as assessed by the treating physician improved significantly between baseline and the end of the study (Fig. 3).


Figure 3
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  		Fig. 3 General condition. General condition of patients on carvedilol treatment (n=116). Data are reported from the start of titration (V1) to the end of the follow-up (V6), P<0.001.

 
3.4. Adverse events and hospitalisations
During the trial 59 patients (41%) experienced 98 minor adverse events (Fig. 4) which were regarded as related to the treatment with carvedilol. The most frequently reported side effects were dizziness, dyspnoea (including exercise-induced dyspnoea) and orthostatic hypotension. A total of nine patients (6%) experienced adverse events regarded as serious by the investigator, six (4%) of these events required hospitalisation, namely cardiac decompensation (n=2), pneumonia (n=2), cerebrovascular accident (n=1) and unclear symptoms (n=1). The three patients who did not require hospitalisation suffered from atrial fibrillation (n=1), increase in symptoms (n=1) and fatigue (n=1). The mean daily dose of carvedilol was 20.8 mg at the time of serious adverse events, which occurred between 12 and 55 days after enrolment. Twenty-nine of the 145 enrolled patients (20%) terminated the study prematurely because of minor side effects (n=12) such as dyspnoea (n=3), dizziness (n=5), bradycardia (n=3) or diarrhea (n=1), or serious adverse events (n=6), namely increase in symptoms (n=1), cardiac decompensation (n=1), unclear symptoms (n=1) (drug related), and cerebrovascular accident (n=1), cardiac decompensation (n=1) and pneumonia (n=1), considered to be drug unrelated. The reasons for the remaining 11 patients who withdrew early from the study were intercurrent illness (n=4), lack of efficiency of the treatment (n=3), non-compliance (n=2), withdrawal of consent (n=1) and unclear symptoms (n=1). 55% (n=16) of the study withdrawals occurred during the first 2 weeks of uptitration (Fig. 1). No major changes in laboratory parameters were observed; serum potassium, sodium and creatinine remained within normal range throughout the study. No patient died.


Figure 4
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  		Fig. 4 Adverse events. Absolute numbers of minor events (n=98) occurring in 59 (41%) of the 145 patients who terminated the study according to protocol.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Previous studies have convincingly shown that patients with moderate to severe heart failure benefit from the addition of carvedilol to therapy with ACE inhibitors and diuretics [2–4,6,10]. Sympathetic activation is a key factor in the pathogenesis of congestive heart failure [7,8]. The benefits observed from continuous long-term betablocker therapy consist of a significant survival advantage compared to placebo, improved ventricular function even with reversal of cardiac remodelling and improvement in mechanical efficiency [1,11–13]. Another important aspect is a socio-economic benefit due to a reduction in hospitalisations for cardiovascular causes, together with a reduction in public health costs [14–16]. Other studies have shown that betablocking agents reduce symptoms of heart failure and improve functional capacity as well as exercise tolerance after myocardial infarction [5].

The present data demonstrate that treatment with carvedilol is well tolerated by patients with chronic heart failure under stable therapy. The initiation of therapy does not require hospitalization, even general practitioners and internists can start carvedilol treatment by administering a low dose of 3.125 mg twice daily for 2 weeks. Since carvedilol inhibits sympathetic activation, the initial loss of inotropic and chronotropic support may lead to transient worsening of CHF. Therefore, titration has to be started with low doses according to the patient's general condition, regular clinical visits at 2-week intervals have to be performed and gradual upward titration has to be considered. If the dose is well tolerated, it is acceptable to double the daily dose at 2-week intervals until the maximal tolerated dose or the maximal dose of 50 mg per day is reached. However, tolerability, compliance and the general condition of the patient must be carefully controlled at 2-week intervals during the titration phase.

Concomitant therapy in this trial was in line with the present guidelines for the treatment of chronic heart failure, namely 90% of patients were receiving a blocker of the RAAS (ACE inhibitors and AT1 receptor antagonists) and 90–99% of patients were on a diuretic. Digitalis was used in nearly a quarter of all patients, aldosterone antagonists in approximately 10% (Table 3).

After the titration phase both the CASA 1- and CASA 2- studies showed clear evidence of improvement in symptoms and state of health [1], which continued during the follow-up phase. Quality of life was analysed and documented by the ‘Minnesota Living with Heart Failure Questionnaire’, which demonstrated a significant reduction in heart failure symptoms such as water retention, impairment of daily activities, shortness of breath, insomnia at night, orthostatic reaction, general fatigue or lack of motivation. The magnitude of this effect is paralleled by the reduction in NYHA classification. The percentage of patients in NYHA-class I rose from approximately 5–30% and was associated with a significant decrease in NYHA-class II from 90 to 65% (Fig. 2). However, there was neither a positive nor a negative effect on patients of NYHA-class III or IV.

Haemodynamic adaptation occurred early and in proportion to the mean carvedilol dose (Fig. 1). Not only did heart rate decrease significantly with each titration step, but systolic and diastolic blood pressure also showed a linear correlation with the mean dose (Table 2). These data confirm a linear dose-response relationship between 2x3.125 mg and 2x25 mg carvedilol for both heart rate and blood pressure, indicating the importance of careful uptitration to the maximal dose of 50 mg carvedilol daily. In this regard, it was interesting to see that when mean dose decreased at the last visit, heart rate and blood pressure increased.

Since there is an initial loss of sympathetic activation at the beginning of treatment with a delayed improvement in ventricular function over a few weeks [17], some patients may become symptomatic and may experience adverse effects during this time. The relatively high incidence of adverse events (41% of all patients) may be explained as follows: patients with severe heart failure and a limited long-term prognosis suffer from an initial decline of LV function, thus leading to potential clinical worsening with an increase in symptoms. However, clinical studies prove the efficacy of long-term treatment with carvedilol in addition to conventional therapy both in patients with moderate and severe heart failure [2,4,18–20]. This results in a remarkable decrease of cardiovascular death and rate of hospitalisations [15,21]. Adverse events frequently occurred during the titration phase (Fig. 1). The most frequently reported symptoms were dizziness, dyspnoea, orthostatic hypotension, bradycardia and gastrointestinal problems. Four patients out of 151 suffered from decompensated heart failure. Although 20% of all patients terminated the study prematurely mainly because of adverse events or worsening of heart failure, in previous studies carvedilol was better tolerated than placebo, reflected by a higher drop-out rate with placebo than in the treatment group [2,3,6,14,19].

In conclusion, our data suggest that carvedilol is safe and well tolerated in patients with stable heart failure under stable concomitant medication with ACE inhibitors and diuretics. Treatment can be initiated by general practitioners and internists on the basis of regular visits during the titration phase and careful watching for side effects and adverse events.


   Acknowledgements
 
This study was supported by an educational grant from Roche Pharmaceuticals Ltd. Switzerland.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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