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• W2783751135 abstract "This article refers to ‘Relationship between heart failure, concurrent chronic obstructive pulmonary disease and beta-blocker use: a Danish nationwide cohort study’, by M. Sessa et al., published in this issue on pages 548–556. The introduction of β-blockers into heart failure with reduced ejection fraction (HFrEF) treatment represented a revolution. Almost 40 years later, they are long accepted as standard therapy in HFrEF.1 They changed the belief that sympathetic activation contributes to stabilizing HFrEF, and rather proved the opposite. With the change of the century, several trials demonstrated the positive effects of several β-blockers to reduce both morbidity and mortality in HFrEF.1 β-Blockers can be classified, depending on their affinity levels for β1- (predominantly present in the heart) and β2-adrenergic receptors (present in vascular and pulmonary smooth muscle), into (i) non-selective β-blockers, which block competitively both receptors, and (ii) selective β-blockers with higher affinity for β1- than β2-receptors. This cardio-selectivity is dose-dependent. Additionally, β-blockers have other actions such as α1-adrenoreceptor blockade (carvedilol, labetalol) producing peripheral vasodilatation, β2-adrenergic receptor agonism (celiprolol), or mechanisms other than blocking adrenoreceptors (bucindolol, nebivolol). These differences between agents may result in non-uniform effects, questioning a single class effect of β-blockers. The disappointing results of bucindolol in the BEST trial indeed suggested that differences between β-blockers might matter. In 2003, the large randomized COMET trial compared the effects of the two β-blockers carvedilol and metoprolol. The carvedilol group showed a significant 17% reduction in mortality as compared to metoprolol.2 Unfortunately, the short working formulation of metoprolol (tartrate) in relatively low dose was used in the COMET trial2 as compared to metoprolol succinate in the MERIT-HF trial,1 resulting in a debate about the relevance of the COMET trial that is still not completely resolved. This debate may be fuelled anew by the publication of a large Danish heart failure cohort, presented in this issue of the Journal.3 Though not intended as the main research question and only investigated in patients also having chronic obstructive pulmonary disease (COPD), the risk of heart failure-related hospitalization was significantly higher with carvedilol compared with the selective β-blockers bisoprolol, metoprolol, and nebivolol, even after multivariable adjustment. These results are not only in contrast to the COMET trial (COPD patients were excluded though)2 but also to other registries that did not find negative effects of carvedilol compared with β1-selective β-blockers,4 or even the opposite;5 the latter study was, interestingly enough, published by the same group as the report in this issue.3 Also, a meta-analysis of randomized trials came to the conclusion that carvedilol and metoprolol similarly reduce mortality.6 Interestingly, all-cause hospitalization was identical in all four groups, which is in line with the other reports.4-6 Thus, one possible explanation for the discrepancy is some uncertainty in classification of hospitalizations, which is also given as a possible reason by the authors.3 In addition, full adjustment is usually not possible in registries such as this one due to the lack of some relevant data, and a not fully identified imbalance between the patient groups is unavoidable. Among other, the paper by Sessa et al.3 lacks data on treatment of heart failure apart from β-blockers. Optimal pharmacological heart failure treatment, including up-titration to the maximum tolerated dose, is associated with a clear benefit in morbidity and mortality.1 When evaluating the effect of non-cardiovascular β-blockers, it is important to evaluate guideline adherence regarding the other heart failure medication as well and it would be important to adjust for imbalance in this regard. Based on the previous literature, it seems rather unlikely that carvedilol may really lead to higher rates of heart failure-related hospitalizations compared with other β-blockers, at least in the general HFrEF population. Whether this is similar in patients with COPD, however, has not been sufficiently studied. COPD is a common co-morbidity in patients with chronic heart failure7 and contributes to morbidity and mortality.1 Similarly, chronic heart failure is frequently present in COPD patients, although often undiagnosed and untreated, and co-morbid chronic heart failure has adverse effects in COPD.8 Given the clinical relevance of concomitant chronic heart failure and COPD, identification and treatment of both conditions in patients who have any of these two is recommended.1, 8 Although β-blockers reduce morbidity and mortality in patients with HFrEF, there is significant concern regarding prescribing these to patients with co-morbid chronic airflow limitation. In the ESC-HFA Heart Failure Long-Term Registry, significantly lower rates of β-blocker use were reported in patients with chronic heart failure and COPD compared with those with chronic heart failure only.9 The primary reason for not prescribing β-blockers in chronic heart failure with vs. without COPD was asthma/bronchospasm.9 Although COPD is defined by the presence of chronic respiratory symptoms and persistent airflow limitation,8 significant spirometric reversibility of this airflow obstruction is present in more than 20% of COPD patients and this disease characteristic varies over time.10 While reversibility status was traditionally used to differentiate between COPD and asthma, recent studies indicated that it is an unreliable and unstable diagnostic criterion.10 Diagnostic challenges, clinical overlap between COPD and asthma, and the presence of reversibility may contribute to the underuse of β-blockers in COPD. Indeed, several studies in patients with COPD have shown effects of β-blockers on pulmonary function, which is in line with the report of the Danish cohort in this issue.3 Thus, risk of hospitalization for COPD was increased after initiation of β-blockade, irrespective of which of the β-blockers was used. However, a meta-analysis pooling the results of 22 randomized, blinded, controlled trials on the use of cardio-selective β-blockers in patients with COPD reported that these produced no significant change in forced expiratory volume in the first second (FEV1) or respiratory symptoms compared with placebo, and did not affect the spirometric response to β2-agonists.11 These findings were unchanged in subgroups of COPD patients with severe airflow limitation or spirometric reversibility.11 Thus, the use of cardio-selective β-blockers is considered safe in COPD and there is no evidence that HFrEF should be treated differently in the presence of COPD.8 The potential, though not proven, small increase in risk of COPD hospitalization after initiation of β-blockers3 is certainly outweighed by the proven beneficial effect on HFrEF. Moreover, there are theoretical reasons why β-blockers could have additional beneficial effects in COPD, including reduction in systemic inflammation and inhibition of adrenergic activation.8 The question arises as to whether there is a clinically relevant difference between the use of β1-selective and non-selective β-blockers. Short-term use of metoprolol or propranolol resulted in increased airway hyper-responsiveness in comparison with placebo, while propranolol also resulted in reduced FEV1 and a hampered bronchodilating effect of an inhaled β2-agonist.12 Jabbour et al. compared carvedilol, metoprolol, and bisoprolol in a triple-crossover trial involving 51 heart failure patients of whom 35 had COPD. Subjects received each β-blocker (carvedilol, metoprolol, or bisoprolol) for 6 weeks before resuming their original β-blocker. This trial showed that switching between β1-selective β-blockers and carvedilol was well tolerated but resulted in changes in airway function (FEV1) that were more pronounced in COPD patients. Central pressure and NT-proBNP level reductions were observed in the carvedilol group.13 A sub-analysis of the OPTIMIZE registry including more than 2600 heart failure patients, 27% of them suffering from COPD, showed that both cardio-selective and non-selective β-blockers were equally effective in both groups.14 However, in patients with chronic heart failure and co-morbid COPD, carvedilol was clinically tolerated by 84% of patients with no significant reversible airflow limitation, while only half of patients with chronic heart failure and asthma tolerated carvedilol.15 This is in line with a retrospective, non-randomized trial analysing long-term outcomes in acute decompensated heart failure patients with COPD, where the rate of heart failure and/or COPD exacerbations was higher in patients treated with carvedilol compared with bisoprolol; however, in a multivariate analysis, only a past history of COPD exacerbations increases the risk of re-hospitalizations due to either heart failure or COPD.16 Taken together, evidence only comes from small studies, registries, or subgroup analyses, and hard evidence is lacking. It suggests that non-selective as compared to cardio-selective β-blockade may induce a small FEV1 reduction, which is usually asymptomatic unless patients have relevant reversibility of airflow limitation. The analysis from the Danish cohort additionally suggests that carvedilol needs to be more often stopped compared with selective β-blockers.3 What may be the clinical consequences of the Danish cohort study published in this issue3 and the other, though limited, evidence regarding the use of β-blockers in HFrEF patients with co-morbid COPD? Although awareness of the safety and tolerability of β-blockers in COPD is increasing, the clinical practice is still falling behind. Thus, all patients with COPD and HFrEF should receive β-blockers, but initiation should be done under close monitoring. There is very little reason to prefer non-selective above β1-selective β-blockers, but important reasons to do the opposite. This is not so much due to the small reduction in FEV1 found in small studies but much more the intolerance of non-selective β-blockers in COPD patients with significant reversibility of airflow limitation. This is not easily predictable. Therefore, despite the limited evidence, the preference for one of the β1-selective blockers proved to be beneficial in HFrEF (i.e. bisoprolol, metoprolol succinate, nebivolol) above carvedilol in COPD patients is no longer in the ‘β-phase’ but should be generally adopted. Conflict of interest: none declared." @default.
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• W2783751135 date "2018-01-12" @default.
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• W2783751135 title "An old debate still in the β-phase?" @default.
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• W2783751135 doi "https://doi.org/10.1002/ejhf.1086" @default.
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