Role of β-blockers in the cardiovascular disease continuum: a collaborative Delphi survey-based consensus from Asia-Pacific

Figures & data

Figure 1. Flowchart representing the sequence of events followed in the present study.

Figure 2. Summary of results from the first round of the Delphi Survey (consensus reached: agreed by ≥70% of experts; majority opinion: agreed by 51–69% of experts; Minority opinion: agreed by ≤50% of the experts).

Figure 3. Summary of results from the combined first and second round of the Delphi survey (consensus reached: agreed by ≥70% of experts; majority opinion: agreed by 51–69% of experts; Minority opinion: agreed by ≤50% of the experts; *Statement 23 was omitted in the final version as consensus was not achieved in both rounds; *Statement 24 suggested by the experts in round-1 which was incorporated in the final version after achieving consensus; #Statement 34 was suggested by the experts in round-1 that was incorporated in the final version after achieving consensus).

Table 1. Scientific statements related to the role of β-blocker therapy in the cardiovascular disease continuum.

#	Scientific statements
Patterns of β-blocker use
1	β-blockers are underutilized or are not used at their target dose or the maximum tolerated dose in patients with HF and comorbid conditions like a chronic obstructive pulmonary disease.
Hypertension
2	Amongst the Asian countries, China, Indonesia, India, Korea, Singapore, and Thailand also recommend β-blockers as a first-line antihypertensive agent.
3	β-blockers are recommended in hypertensive patients with compelling indications such as HF, angina, post-MI or CAD, AF, and younger hypertensive pregnant women or hypertensive women planning pregnancy.
4	Given that patients with hypertension reportedly have elevated HR in Asia-pacific countries, β-blockers should be recommended in young patients (<60 years) with such a sympathetic overdrive.
5	As recommended by the hypertension management guidelines, highly selective β-blockers such as bisoprolol are effective antihypertensive agents. Bisoprolol, as a representative β-blocker, is recommended for patients with resistant hypertension in addition to other medications, especially when patients are intolerant to mineralocorticoid receptor antagonists.
6	Selective β1 receptor blockers like bisoprolol produce effective regression of left ventricular hypertrophy, therefore, they may be re-evaluated in hypertension guidelines in the future for patients with left ventricular hypertrophy.
7	Selective β1 blockers like bisoprolol provide greater BP control including central aortic BP than atenolol, particularly more effective in reducing systolic BP and diastolic BP during the final 4 hours of dosing interval and greater BP control in smoker hypertensives.
8	Bisoprolol provides a similar magnitude of BP lowering compared to Nebivolol despite the nitric oxide release property associated with Nebivolol (Nebis study); in addition, bisoprolol was associated with a stronger effect of HR reduction than nebivolol in the 3rd hour after administration.
9	Bisoprolol provides stronger HR reduction for 24 hours than metoprolol SR and non-inferior dynamic BP reduction vs. metoprolol SR in patients with mild-to-moderate hypertension, in another study bisoprolol, had significant reductions in systolic BP compared to metoprolol tartrate.
10	There is a trend toward favoring bisoprolol for survival benefits compared to other β-blockers. In one primary care real-world setting study, treatment with a highly-cardioselective β-blocker, bisoprolol, was associated with a reduced risk of mortality in patients with hypertension as compared with other β-blockers.
HF
Heart failure reduced ejection fraction (HFrEF)
11	β-blockers are recommended as first-line treatment in patients with HFrEF to reduce all-cause mortality, CV mortality, and HF-related hospitalization. Consistent benefits have been observed by age, sex, cause (i.e., ischemic vs. non-ischemic cardiomyopathy), degree of symptoms, and degree of systolic dysfunction. They also improved left ventricular function.
12	Based on current clinical evidence, HF management guidelines recommend only three evidence-based β-blockers, namely, bisoprolol, carvedilol, and metoprolol succinate, for treating patients with HFrEF.
13	To achieve optimal benefits, it is recommended to titrate the dose of β-blockers to the target dose or the maximally tolerated dose.
14	Bisoprolol may be superior to carvedilol in protecting from myocardial injury and preserving pulmonary function in patients with HFrEF.
Role in combination with other HF medications
15	Given that ARNI is increasingly used in managing patients with HF for patients vulnerable to hypotension with ARNI and carvedilol, bisoprolol could be a better choice for combination therapy.
16	In patients with HF experiencing hypotension or dizziness with carvedilol, they can be switched to bisoprolol, allowing them to reach the target dose and improve New York Heart Association class.
Acute HF
17	In patients undergoing long-term β-blocker therapy who present with acute HF exacerbation, available data suggest that withdrawing β-blockers might worsen clinical outcomes and, therefore, should be continued unless there is a risk for hemodynamic compromise and re-introduced as soon as the patient is hemodynamically stable.
CAD
18	Oral β-blockers within the first 24 h of ST-elevation MI and non-ST-elevation MI, in the absence of HF, low output state, the risk for cardiogenic shock, or other contraindications to β blockade.
19	The duration of β-blocker therapy remains debatable as no study has evaluated it in patients with acute coronary syndrome without HF, but the available evidence suggests β-blocker use for up to 3 years.
20	All patients with chronic stable ischemic heart disease should receive long-term treatment with β-blockers to control ischemia, prevent infarction, and improve survival.
21	In patients with stable angina without prior MI, β-blockers are recommended for providing relief from angina symptoms and for reducing the ischemic burden.
22	Bisoprolol is one of the most commonly used β-blockers in patients after acute coronary syndrome and in patients with stable CAD in most parts of the world in primary care real-world settings.
23	While non-selective beta-blockers are preferred in patients with cirrhosis, the use of β1-selective blockers was associated with lower risks of major cardiac and cerebrovascular events as documented in patients with cirrhosis with coexistent acute myocardial infarction in a 13-year nationwide population-based study in Asia.
Comorbidities
HF and renal function
24^a	β-blockers should be used in patients with HFrEF in sinus rhythm with co-existent chronic kidney disease including those undergoing hemodialysis to reduce mortality and hospitalization.
25	Cardioselective β-blockers like bisoprolol are associated with superior survival benefits compared to other β-blockers such as metoprolol and carvedilol in high-risk patients, like those receiving maintenance hemodialysis.
Chronic obstructive pulmonary disease/asthma and cardiovascular disease
26	β-blocker use is associated with reduced in-hospital and all-cause mortality among patients with chronic obstructive pulmonary disease and cardiovascular disease.
27	β1 selective β-blockers in chronic obstructive pulmonary disease patients do not have significant adverse effects on lung function (FEV1), respiratory symptoms, or response to β2-agonists even in patients with advanced disease.
28	In patients with HFrEF and comorbid chronic obstructive pulmonary disease, current evidence and clinical practice guidelines recommend highly cardioselective bisoprolol to reduce all-cause mortality and the risk for re-hospitalization due to chronic HF and/or chronic obstructive pulmonary disease exacerbation as compared to carvedilol.
29	Compared with non-users, highly cardioselective β-blockers, bisoprolol is associated with a significantly better dose-dependent survival outcome in patients with HF and chronic obstructive pulmonary disease.
The safety profile of β-blockers
30	Highly cardioselective β-blockers (bisoprolol) do not increase airways resistance compared to atenolol and placebo, suggesting that the risk for bronchoconstriction decreases with increasing β1-selectivity; additionally, bisoprolol has shown minimal effects on lung function in patients with stable angina pectoris and chronic obstructive pulmonary disease.
31	Highly cardioselective β-blockers (bisoprolol) have minimal effects on glucose and lipid metabolism.
32	Highly cardioselective β-1 blockers like bisoprolol have minimal effect on male sexual function.
33^b	Beta-blockers with higher lipid solubility are associated with higher CNS side-effects such as hallucinations and sleeplessness.
Pharmacokinetic variability and β-1 selectivity
34	Bisoprolol has higher β-1 selectivity and a consistent pharmacokinetic profile compared to other β-blockers such as atenolol, carvedilol, and metoprolol.
35	Studies of the β1- vs. β2-adrenoceptor selectivity of bisoprolol and nebivolol have provided conflicting results. Nebivolol was found to be about 3-fold more selective than bisoprolol for the β1- vs. β2-adrenoceptor in the human myocardium. In another study, radioligand binding studies reveal 3- to 4-fold β1 selectivity for nebivolol and 16- to 20-fold β1 selectivity for bisoprolol in human myocardium, documenting higher β1 with bisoprolol. Additionally, nebivolol (but not bisoprolol) exerts intrinsic sympathomimetic activity at the β3-adrenoceptor. This action may account for observations of a lesser effect of nebivolol in reducing HR, compared with bisoprolol.
36	Among the commonly used β-blockers, bisoprolol has shown the lowest interindividual pharmacokinetic variability.

^aStatement #24 was suggested by the experts in round 1 andwas incorporated in the final version after achieving consensus.

^bStatement #33 was suggested by the experts in round 1 and was incorporated in the final version after achieving consensus.