Beta-blockade today: the gap between evidence and practice
Department of Internal Medicine, University Hospital Zürich, Office HAL 16, D 2, Raemistrasse 100, CH 8091 Zürich, Switzerland
* Corresponding author. Tel: +41 44 255 9305; fax: +41 44 255 4554. E-mail address: ferenc.follath{at}usz.ch
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Abstract |
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 Top Abstract IntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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Current European Society of Cardiology guidelines for chronic heart failure (CHF) recommend the use of beta-blockers in all symptomatic patients with systolic dysfunction. Beta-blockers reduce CHF mortality by >30% and also reduce hospitalizations. Given at appropriate doses, they are generally well tolerated, even in the elderly. However, two large European surveys [IMPROVEMENT in primary care and Euro Heart Failure Survey (EURO-HF) in hospitalized patients] show that beta-blockers are used in only 34–37% of patients, with a wide variation between countries. The frequency of beta-blocker prescription in patients
75 years of age is <20%. A recent analysis of EURO-HF showed that, even among CHF patients who met the criteria for the landmark trials, without comorbidities or other risk factors, beta-blockers are used in <50% of cases. General practitioners and internists prescribe beta-blockers less frequently than cardiologists. This difference may be partly due to the fact that patients treated by non-specialists tend to be older and have more comorbidities. Another problem is the fear of side effects with beta-blockers. This is often due to lack of experience (particularly among primary care physicians), as in the past beta-blockers were considered contraindicated in CHF. Frequently cited reasons for not prescribing beta-blockers are advanced age, severe symptoms, and comorbidities (e.g. chronic lung disease, diabetes). In fact, most problems can be avoided if beta-blockers are started at a very low dose and titrated up step by step to the maximum tolerated dose. Mortality benefits are achieved even at doses much lower than the targets used in clinical trials. The CIBIS III results should now help to eliminate most of the doubts regarding the efficacy and tolerability of beta-blockade, even in the elderly patient population.
Key Words: Beta-blockers • Randomized controlled trials • Surveys • Clinical practice • Chronic heart failure
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Introduction |
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TopAbstractIntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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The European Society of Cardiology (ESC) guidelines for heart failure were updated in May 20051 and were recently followed by new American Heart Association/American College of Cardiology (ACC/AHA) guidelines.2 In these guidelines, ACE-inhibitors are recommended as first-line therapy for chronic heart failure (CHF). Beta-blockers are also recommended for all patients with symptomatic stable mild, moderate to severe CHF (NYHA classes II–IV), on standard treatment with ACE-inhibitors and diuretics, unless there is a contraindication. They are also recommended in patients with left ventricular (LV) systolic dysfunction following myocardial infarction, regardless of whether symptomatic CHF is present, in addition to ACE-inhibitors. ACC/AHA guidelines also recommend that all patients with LV dysfunction and a reduced LV ejection fraction (LVEF) should receive beta-blockers. These recommendations are based on the dramatic reductions achieved in mortality and hospitalization rates in the major beta-blocker trials.
The importance of using a beta-blocker as well as an ACE-inhibitor is underlined by post hoc analysis3 of the SOLVD prevention and treatment trials.4,5 The main objective of these trials was to test the effect of the ACE-inhibitor enalapril on morbidity and mortality in asymptomatic patients with reduced LVEF (prevention4) and in patients with symptomatic CHF and reduced LVEF (treatment5). However, in the prevention trial, mortality was only reduced in patients who were also receiving a beta-blocker. In the treatment trial, combination treatment had the greatest effect on mortality, followed by beta-blockade alone and enalapril alone (Figure 1).3
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Thus, there is a convincing argument that both drug classes should be given as early as possible in CHF. The recent CIBIS III trial shows that initiating treatment of CHF with the beta1-selective beta-blocker bisoprolol is as effective and well tolerated as starting treatment with an ACE-inhibitor (enalpril).6,7 CIBIS III also suggests that initiating beta-blockade first might increase survival in the early phase of treatment, allowing a greater number of patients to subsequently benefit from combination therapy.7
Yet, recent surveys show that clinical practice continues to lag far behind the evidence-based recommendations given in current guidelines. As we enter the 21st century, beta-blockers are the most under-prescribed of all the preventive treatments recommended in CHF, being given to only about one-third of eligible patients in Europe.8,9 This review examines the evidence regarding the under-prescription of beta-blockers, suggests some possible reasons for it, and discusses how the use of beta-blockers in CHF might be extended and improved to benefit a greater number and wider spectrum of patients.
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European surveys of CHF treatment |
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TopAbstractIntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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Two recent surveys, the Euro Heart Failure Survey (EURO-HF8) and the IMPROVEMENT of Heart Failure Programme9 provide up-to-date information on how CHF is managed in Europe. EURO-HF was conducted to ascertain how hospitalized patients are managed. It screened the discharge summaries of 11 304 patients over a 6-week period in 2000–01, covering 115 hospitals from 24 European countries. The mean age of the patients surveyed was 73 years, and 53% were male. IMPROVEMENT collected data on the management of CHF patients in primary care in 15 European countries in 1999–2000. In total, 1363 physicians provided data for 11 062 patients with a mean age of 70 years, 55% of whom were male.
IMPROVEMENT and EURO-HF show that beta-blockers are widely under-used, both at hospital discharge and in primary care. Overall beta-blocker usage was similar in both surveys: beta-blockers were used in only one-third of patients (37% in EURO-HF and 34% in IMPROVEMENT), whereas ACE-inhibitors were used in approximately two-thirds (Table 1). IMPROVEMENT showed that beta-blocker prescription rates in primary care varied widely between countries, from 10% in Turkey to 56% in Hungary.9 In this study, only one-fifth of patients received an ACE-inhibitor and beta-blocker in combination.
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Moreover, even when beta-blockers are prescribed, they are often given at doses well below the targets recommended in ESC guidelines.1 EURO-HF8 found that average doses were bisoprolol 4.7 mg daily (vs. the 10 mg daily target dose in the ESC guidelines), metoprolol succinate CR/XL 74.9 mg daily (vs. 200 mg daily) and carvedilol 17.6 mg daily (vs. 50 mg daily). The full recommended dose was used in fewer than 20% of patients (Figure 2). However, as discussed subsequently, this may reflect differences in patient profiles between clinical trials and everyday practice.
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Both surveys show that beta-blocker prescription rates are lower in elderly patients, women, and those with comorbidities. In EURO-HF, the odds ratio for receiving a beta-blocker was reduced in patients >70 years and in those with respiratory disease. Patients were also less likely to receive a beta-blocker if they had non-ischaemic heart failure or if they were female.8 Similarly, IMPROVEMENT showed that beta-blocker prescription rates declined with age (Figure 3), whereas little decline was noted in the prescription of ACE-inhibitors or angiotensin II receptor blockers in elderly patients (unpublished results). IMPROVEMENT also found that patients
75 years had a substantial reduction in the odds of receiving a beta-blocker in combination with an ACE-inhibitor, compared with younger patients. Concomitant disease (stroke, transient ischaemic attack, lung disease, or peripheral vascular disease) was also associated with a reduced likelihood of beta-blocker/ACE-inhibitor combination treatment.9
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What reasons underlie the real-life prescription of beta-blockers in fewer patients and at lower doses than those used in clinical trials? Part of the reason may be a delay, particularly among general internists and primary care physicians, in recognizing that although beta-blockers were previously contraindicated in CHF, they are now firmly indicated. In IMPROVEMENT, only
60% of physicians were aware of the symptomatic and prognostic benefits of beta-blockers compared with 90% for ACE-inhibitors, though there were large differences between countries.9 Some physicians may also be unduly concerned about the risk of transient deterioration of symptoms on the initiation of beta-blocker treatment. Education is therefore still needed regarding the importance and benefits of beta-blockade in CHF. However, there are other important reasons for the disparity between guideline recommendations and beta-blocker usage in real life, as discussed subsequently. First, the patients encountered in routine practice have different characteristics from the selected population included in the landmark trials. Secondly, the objectives of everyday management of CHF are somewhat different from those of clinical trials.
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Real-life patients vs. clinical trials |
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TopAbstractIntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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The disparity between real-life patients and those included in the randomized controlled trials (on which guidelines are based) may contribute to the under-use of beta-blockers (Table 2). However, it should be noted that this cannot be a complete explanation; a recent analysis of the EURO-HF data found that beta-blocker use was only 50% in real-life patients who met the criteria for entry in the landmark trials. Although this is more than the 37% beta-blocker usage rate in the overall CHF population, it is still far too low.
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Age
Patients in most of the major beta-blocker trials10–12 were younger than those encountered in everyday practice. The average age of patients was 70 years in EURO-HF8 and 73 years in IMPROVEMENT,9 whereas it was 61 years in CIBIS II,10 65 years in MERIT-HF,11 and 63 years in COPERNICUS.12 However, the mean ages of patients in SENIORS (76 years)13 and in CIBIS III (72 years)6,7 were representative of CHF patients in the general population.
Elderly patients are more sensitive to the effects of beta-blockade than younger patients and are more likely to suffer adverse events, making up-titration more difficult. However, it should be emphasized that age is not in itself a contraindication to beta-blockade. Some physicians may believe that elderly patients benefit less from beta-blockers than younger patients, but this is incorrect. A recent meta-analysis of all-cause mortality data from elderly and non-elderly CHF patients from five beta-blocker trials revealed that both age groups derived considerable prognostic benefit from beta-blocker therapy, with no statistically significant difference in mortality reduction between the two groups.14
Subgroup analysis of CIBIS II showed that elderly patients benefit as much from beta-blockade with bisoprolol as younger patients.15 Similarly, subgroup analysis of MERIT-HF showed that metoprolol CR/XL improved survival and reduced hospitalizations due to worsening CHF in elderly patients.16 The benefit of metoprolol CR/XL was similar in elderly patients (65 years) with advanced CHF, and in patients 75 years, compared with all patients randomized. Moreover, metoprolol CR/XL was also well tolerated in elderly patients, as evidenced by fewer drug withdrawals in comparison with placebo, regardless of age and severity of heart failure.
Because CHF is more common in elderly patients, and because mortality from CHF also increases sharply with age, the potential benefit of beta-blockade in this age group is high. These are the patients in whom beta-blockade will have the greatest impact in terms of the number of lives saved and the number of hospitalizations avoided.16 From both the individual and the public health point of view, it is important to make every effort to initiate beta-blocker therapy in elderly patients with CHF. However, it should be recognized that elderly patients may not be able to tolerate high doses of beta-blockers and that dose titration should be very gradual in order to maximize tolerability (discussed subsequently).
Sex
Patients in the landmark beta-blocker trials were predominantly male (80% in CIBIS II,10 78% in MERIT-HF,11 and 80% in COPERNICUS12). In contrast, only 53% of patients in EURO-HF8 and 55% in IMPROVEMENT9 were male. In everyday practice, women predominate in the >75 age group (in EURO-HF,8 51% of women were aged 75, compared with only 30% of men). EURO-HF found that women were less likely to receive beta-blockers than men.8 Yet, pooling of mortality results from MERIT-HF, CIBIS II, and COPERNICUS showed very similar survival benefits in women and men with documented systolic heart failure.17 Female sex should not therefore constitute any barrier to the prescription of beta-blockers.
Comorbidities
Patients with comorbidities such as chronic obstructive pulmonary disease, renal and hepatic disease, and diabetes mellitus have usually been excluded from clinical trials, whereas these diseases are common in the real-life heart failure population (Table 3). In a multivariate analysis of IMPROVEMENT, patients with pulmonary disease were less likely to receive a beta-blocker (odds ratio 0.64, 95% confidence interval 0.57–0.72). However, it should be noted that beta-blockers are not in fact contraindicated in chronic obstructive pulmonary disease, although they should not be used in asthma. Subgroup analysis of CIBIS II showed that patients who were diabetic had renal impairment or had NYHA class IV symptoms benefited as much from beta-blockade as those without.
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Variations between cardiologists and other physicians |
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TopAbstractIntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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There are variations in management of CHF between different types of physician. In IMPROVEMENT, only about one-fifth of patients who received beta-blockers had this treatment started by primary care physicians, whereas cardiologists initiated treatment with beta-blockers in over half of all cases.9 Similarly, in EURO-HF, patients were nearly twice as likely to receive a beta-blocker if they were treated by a cardiologist rather than a general internist (Figure 4).3 Variations in prescribing between specialties may be partly due to differing levels of knowledge and confidence. Uncertainty about how to manage elderly patients and those with concomitant diseases such as diabetes and renal failure probably plays a major role in the under-prescription of beta-blockers, especially among non-cardiologists.
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In contrast, a lower rate of prescription of beta-blockers by general internists and primary care physicians may reflect the fact that they treat different patient groups. Data from a Canadian study suggest that the patients treated by general internists are likely to be significantly older and to have more comorbidities than those treated by cardiologists (Table 4).18
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Differing treatment objectives |
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TopAbstractIntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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Furthermore, it should be noted that the objectives of physicians in everyday practice (and those of their patients) differ from those of clinical trials. The landmark trials were concerned mainly with mortality, hospitalization rates, NYHA class (which does reflect quality of life), and, in some trials, exercise performance. In contrast, although practising physicians are also concerned with these outcomes, their immediate concerns are more likely to be symptom reduction and the patient's general well-being.
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Increasing the prescription of beta-blockers: the need for individualized dosing |
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TopAbstractIntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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Recently, the Medical Management of Chronic Heart Failure in Europe and its Related Costs (MAHLER) study showed that just over 60% of cardiologists in Europe adhere to the current ESC heart failure guidelines.19 Hospitalization rates were lower when physicians did adhere to the guidelines, validating the guidelines and implying that an educational effort is needed to bring treatment closer to the guideline recommendations. It is clear that physicians, particularly generalists, should prescribe beta-blockers more frequently in older patients, women, and those with comorbidities. This may be easier to achieve if we do not primarily aim for the maximum target doses used in the landmark trials, but instead aim to up-titrate the beta-blocker to the maximum tolerated dose.
Although beta-blockers have been well tolerated overall in the landmark trials, there is no doubt that side effects become increasingly frequent at higher doses, especially in elderly patients and those with comorbidities. In the COMET trial,20 in which every effort was made to titrate the beta-blockers as close as possible to target levels, 94% of patients receiving carvedilol experienced at least one adverse event and 75% at least one serious adverse event; corresponding figures for metoprolol were 96% and 77%. Although undoubtedly many of these adverse events were unrelated to the study drug, the data emphasize that tolerability is a genuine concern.
However, evidence is accumulating that beta-blockers save lives even when used at low doses. As detailed by Simon and coworkers21 elsewhere in this article, an analysis of CIBIS II data has shown that bisoprolol reduces mortality, regardless of whether it is used at low, moderate, or high doses. Compared with patients treated with moderate and high doses of bisoprolol, those receiving low doses were significantly older and had more severe CHF and a lower systolic and diastolic blood pressure.
Individual patients vary in their sensitivity to beta-blockers, which means that a similar degree of beta-blockade can be reached at different doses in different individuals. Side effects may begin to arise after maximum receptor occupancy is reached. A post hoc analysis of MERIT-HF data compared heart rate response and clinical outcomes in subgroups who were titrated up to more vs. less than 100 mg of metoprolol CR/XL once daily.22 Heart rate was reduced to a similar degree in the two dose groups, indicating greater sensitivity to beta-blockade in the low-dose group. Moreover, both groups showed a similar reduction in total mortality. Thus, physicians can be reassured that it is worthwhile initiating and persisting with a beta-blocker, even if the patient can only tolerate a very low dose. Genuine contraindications are few, but it is especially important in elderly patients, those with severe CHF, and those with comorbidities to start at a very low dose and up-titrate it as slowly as may be necessary.
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Conclusions |
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TopAbstractIntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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Evidence-based guidelines remain the scientific foundation for management of CHF, but in everyday practice, they cannot be applied rigidly. Very often it is not the drug but the dose that is not tolerated. It is better to give a low dose of a beta-blocker than none at all. Individualization of dosage is critical to allow all eligible patients, including the elderly, to benefit from beta-blockade. In future, clinical trials in CHF should include more elderly patients, women, and those with comorbidities. CIBIS III is among the first trials to follow this principle and include such ‘real-life patients,’ and it has clearly demonstrated that beta-blockers are effective and well tolerated, regardless of age. It also shows that initiating a beta-blocker first is as effective and safe as initiating an ACE-inhibitor first. The option to up-titrate the beta-blocker first, in the absence of an ACE-inhibitor, may encourage physicians to use beta-blockers more often in the elderly and patients with comorbidities and contribute to the wider use of beta-blockers in everyday clinical practice.
Conflict of interest: F. Follath received honoraria for lectures from Merck, Germany.
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References |
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TopAbstractIntroductionEuropean surveys of CHF...Real-life patients vs. clinical...Variations between cardiologists...Differing treatment objectivesIncreasing the prescription of...ConclusionsReferences |
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